Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme

ABSTRACT

The present invention relates to inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme and their use in treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, central nervous system disorders, and diseases and conditions that are related to excessive glucocorticoids.

This application is a continuation-in-part application of U.S.Non-Provisional patent application Ser. No. 12/355,909, filed Jan. 19,2009, which is a continuation application of U.S. Non-Provisional patentapplication Ser. No. 11/325,965, filed Jan. 5, 2006, which claimspriority from U.S. Provisional Patent Application Ser. No. 60/641,520,filed Jan. 5, 2005, which are incorporated herein by reference. Also,this application is a continuation-in-part of U.S. Non-Provisionalpatent application Ser. No. 12/195,937, filed Aug. 21, 2008, whichclaims priority from U.S. Provisional Patent Application Ser. No.60/957,082, filed Aug. 21, 2007, which are hereby incorporated byreference.

FIELD OF INVENTION

The present invention relates to compounds that are inhibitors of the11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The presentinvention further relates to the use of inhibitors of11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment ofnon-insulin dependent type 2 diabetes, insulin resistance, obesity,lipid disorders, metabolic syndrome, disorders and deficits of thecentral nervous system associated with diabetes, associated with agingand neurodegeneration, comprising attention deficit disorder in general,attention deficit hyperactivity disorder (ADHD), Alzheimer's disease(AD), mild cognitive impairment, senile dementia, AIDS dementia,neurodegeneration, depression, and schizophrenia, and other diseases andconditions that are mediated by excessive glucocorticoid action.

BACKGROUND OF THE INVENTION

Insulin is a hormone that modulates glucose and lipid metabolism.Impaired action of insulin (i.e., insulin resistance) results in reducedinsulin-induced glucose uptake, oxidation and storage, reducedinsulin-dependent suppression of fatty acid release from adipose tissue(i.e., lipolysis) and reduced insulin-mediated suppression of hepaticglucose production and secretion. Insulin resistance frequently occursin diseases that lead to increased and premature morbidity andmortality.

Diabetes mellitus is characterized by an elevation of plasma glucoselevels (hyperglycemia) in the fasting state or after administration ofglucose during a glucose tolerance test. While this disease may becaused by several underlying factors, it is generally grouped into twocategories, Type 1 and Type 2 diabetes. Type 1 diabetes, also referredto as Insulin Dependent Diabetes Mellitus (“IDDM”), is caused by areduction of production and secretion of insulin. In type 2 diabetes,also referred to as non-insulin dependent diabetes mellitus, or NIDDM,insulin resistance is a significant pathogenic factor in the developmentof hyperglycemia. Typically, the insulin levels in type 2 diabetespatients are elevated (i.e., hyperinsulinemia), but this compensatoryincrease is not sufficient to overcome the insulin resistance.Persistent or uncontrolled hyperglycemia in both type 1 and type 2diabetes mellitus is associated with increased incidence ofmacrovascular and/or microvascular complications includingatherosclerosis, coronary heart disease, peripheral vascular disease,stroke, nephropathy, neuropathy and retinopathy.

Insulin resistance, even in the absence of profound hyperglycemia, is acomponent of the metabolic syndrome. Recently, diagnostic criteria formetabolic syndrome have been established. To qualify a patient as havingmetabolic syndrome, three out of the five following criteria must bemet: elevated blood pressure above 130/85 mmHg, fasting blood glucoseabove 110 mg/dl, abdominal obesity above 40″ (men) or 35″ (women) waistcircumference and blood lipid changes as defined by an increase intriglycerides above 150 mg/dl or decreased HDL cholesterol below 40mg/dl (men) or 50 mg/dl (women). It is currently estimated that 50million adults, in the US alone, fulfill these criteria. Thatpopulation, whether or not they develop overt diabetes mellitus, are atincreased risk of developing the macrovascular and microvascularcomplications of type 2 diabetes listed above.

Available treatments for type 2 diabetes have recognized limitations.Diet and physical exercise can have profound beneficial effects in type2 diabetes patients, but compliance is poor. Even in patients havinggood compliance, other forms of therapy may be required to furtherimprove glucose and lipid metabolism.

One therapeutic strategy is to increase insulin levels to overcomeinsulin resistance. This may be achieved through direct injection ofinsulin or through stimulation of the endogenous insulin secretion inpancreatic beta cells. Sulfonylureas (e.g., tolbutamide and glipizide)or meglitinide are examples of drugs that stimulate insulin secretion(i.e., insulin secretagogues) thereby increasing circulating insulinconcentrations high enough to stimulate insulin-resistant tissue.However, insulin and insulin secretagogues may lead to dangerously lowglucose concentrations (i.e., hypoglycemia). In addition, insulinsecretagogues frequently lose therapeutic potency over time.

Two biguanides, metformin and phenformin, may improve insulinsensitivity and glucose metabolism in diabetic patients. However, themechanism of action is not well understood. Both compounds may lead tolactic acidosis and gastrointestinal side effects (e.g., nausea ordiarrhea).

Alpha-glucosidase inhibitors (e.g., acarbose) may delay carbohydrateabsorption from the gut after meals, which may in turn lower bloodglucose levels, particularly in the postprandial period. Likebiguanides, these compounds may also cause gastrointestinal sideeffects.

Glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a newer class ofcompounds used in the treatment of type 2 diabetes. These agents mayreduce insulin resistance in multiple tissues, thus lowering bloodglucose. The risk of hypoglycemia may also be avoided. Glitazones modifythe activity of the Peroxisome Proliferator Activated Receptor (“PPAR”)gamma subtype. PPAR is currently believed to be the primary therapeutictarget for the main mechanism of action for the beneficial effects ofthese compounds. Other modulators of the PPAR family of proteins arecurrently in development for the treatment of type 2 diabetes and/ordyslipidemia. Marketed glitazones suffer from side effects includingbodyweight gain and peripheral edema.

Additional treatments to normalize blood glucose levels in patients withdiabetes mellitus are needed. Other therapeutic strategies are beingexplored. For example, research is being conducted concerningGlucagon-Like Peptide 1 (“GLP-1”) analogues and inhibitors of DipeptidylPeptidase IV (“DPP-IV”) that increase insulin secretion. Other examplesinclude: Inhibitors of key enzymes involved in the hepatic glucoseproduction and secretion (e.g., fructose-1,6-bisphosphatase inhibitors)and direct modulation of enzymes involved in insulin signaling (e.g.,Protein Tyrosine Phosphatase-1B, or “PTP-1B”).

Another method of treating or prophylactically treating diabetesmellitus includes using inhibitors of 11-β-hydroxysteroid dehydrogenaseType 1 (11β-HSD1). Such methods are discussed in J. R. Seckl et al.,Endocrinology, 142: 1371-1376, 2001 and references cited therein.Glucocorticoids are steroid hormones that are potent regulators ofglucose and lipid metabolism. Excessive glucocorticoid action may leadto insulin resistance, type 2 diabetes, dyslipidemia, increasedabdominal obesity and hypertension. Glucocorticoids circulate in theblood in an active form (i.e., cortisol in humans) and an inactive form(i.e., cortisone in humans). 11β-HSD1, which is highly expressed inliver and adipose tissue, converts cortisone to cortisol leading tohigher local concentration of cortisol. Inhibition of 11β-HSD1 preventsor decreases the tissue specific amplification of glucocorticoid actionthus imparting beneficial effects on blood pressure and glucose- andlipid-metabolism.

11β-HSD-1 is a low affinity enzyme with K_(m) for cortisone in themicromolar range that prefers NADPH/NADP⁺ (nicotinamide adeninedinucleotide phosphate) as cofactors. 11β-HSD-1 is widely expressed andparticularly high expression levels are found in liver, brain, lung,adipose tissue, and vascular smooth muscle cells. In vitro studiesindicate that 11β-HSD-1 is capable of acting both as a reductase and adehydrogenase.

However, many studies have shown that it functions primarily as areductase in vivo and in intact cells. It converts inactive11-ketoglucocorticoids (i.e., cortisone or dehydrocorticosterone) toactive 1-hydroxyglucocorticoids (i.e., cortisol or corticosterone), andthereby amplifies glucocorticoid action in a tissue-specific manner.

11β-HSD-1 is expressed in mammalian brain, and published data indicatesthat elevated levels of glucocorticoids may cause neuronal degenerationand dysfunction, particularly in the aged (de Quervain et al., Hum Mol.Genet., 13, 47-52 (2004); Belanoff et al. J. Psychiatr Res., 35, 127-35,(2001)). Evidence in rodents and humans suggests that prolongedelevation of plasma glucocorticoid levels impairs cognitive functionthat becomes more profound with aging. (A. M. Issa et al., J. Neurosci.,10, 3247-3254 (1990); S. J. Lupien et. al., Nat. Neurosci., 1, 69-73(1998); J. L. Yau et al., Neuroscience, 66, 571-581 (1995)). Chronicexcessive cortisol levels in the brain may result in neuronal loss andneuronal dysfunction. (D. S. Kerr et al., Psychobiology, 22, 123-133(1994); C. Woolley, Brain Res., 531, 225-231, (1990); P. W. Landfield,Science, 272, 1249-1251 (1996)). Furthermore, glucocorticoid-inducedacute psychosis exemplifies a more pharmacological induction of thisresponse, and is of major concern to physicians when treating patientswith these steroidal agents (Wolkowitz et al.; Ann NY Acad. Sci., 1032,191-194 (2004)). It has been recently shown that 11β-HSD-1 mRNA isexpressed in human hippocampus, frontal cortex and cerebellum, and thattreatment of elderly diabetic individuals with the non-selective11β-HSD-1 and 11β-HSD-2 inhibitor carbenoxolone improved verbal fluencyand memory (Thekkapat et al., Proc Natl Acad Sci USA, 101, 6743-6749(2004)). Excessive glucocorticoid levels also affects psychopathology,as shown in animal models, it leads to increased anxiety and aggression.Chronic elevation of cortisol has been also associated with depressionin Cushing's disease (McEwen, Metab. Clin. & Exp., 54, 20-23 (2005)). Anumber of animal and clinical studies have provided evidence for thecorrelation between increases in glucocorticoid levels andneuropsychiatric disorders such as major depressive disorder, psychoticdepression, anxiety, panic disorder, post traumatic stress disorder, anddepression in Cushing's syndrome (Budziszewska, Polish J. of Pharmacol.,54, 343-349, (2002); Ströhle et al., Pharmacopsychiatry Vol. 36,S207-S214, 2003; DeBattista et al., TRENDS in Endocr. Metab., 17,117-120 (2006); Normanet al., Expert Rev. Neurotherapeutics, Vol. 7,pages 203-213 (2007)).

Thus, inhibiting 11β-HSD1 benefits patients suffering from non-insulindependent type 2 diabetes, insulin resistance, obesity, lipid disorders,metabolic syndrome, central nervous system disorders, age-related orglucocorticoid-related declines in cognitive function such as those seenin Alzheimer's and associated dementias, major depressive disorder,psychotic depression, anxiety, panic disorder, post traumatic stressdisorder, depression in Cushing's syndrome, and treatment resistantdepression, and other diseases and conditions mediated by excessiveglucocorticoid action.

SUMMARY OF THE INVENTION

All patents, patent applications and literature references cited in thespecification are herein incorporated by reference in their entirety.

One aspect of the present invention is directed toward a compound offormula (I)

wherein

A¹, A², A³ and A⁴ are each individually selected from the groupconsisting of hydrogen, alkenyl, alkyl, alkyl-NH-alkyl, alkylcarbonyl,alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cyano, cycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxyalkyl,arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocycleoxyalkyl, heterocyclesulfonyl, halogen, haloalkyl,—NR⁵—[C(R⁶R⁷)]_(n)—C(O)—R⁸, —O—[C(R⁹R¹⁰)]_(p)—C(O)—R¹¹, —OR¹², —S-alkyl,—S(O)-alkyl, —N(R¹³R¹⁴), —CO₂R⁵, —C(O)—N(R¹⁶R¹⁷), —C(R¹⁸R¹⁹)—OR²⁰,—C(R²¹R²²)—N(R²³R²⁴), —C(═NOH)—N(H)₂, —C(R^(18a)R^(19a))—C(O)N(R²³R²⁴),—S(O)₂—N(R²⁵R²⁶), and —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶);

R^(18a) and R^(19a) are each independently selected from the groupconsisting of hydrogen and alkyl;

n is 0 or 1;

p is 0 or 1;

D is a member selected from the group consisting of a —O—, —S—, —S(O)—and —S(O)₂—;

E is a member selected from the group consisting of alkyl, alkoxyalkyl,carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle,heterocyclealkyl, or R⁴ and E taken together with the atoms to whichthey are attached form a heterocycle;

R¹ is a member selected from the group consisting of hydrogen and alkyl;

R² is a member selected from the group consisting of hydrogen, alkyl andcycloalkyl;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle andheterocyclealkyl, or R³ and R⁴ taken together with the atoms to whichthey are attached form a ring selected from the group consisting ofcycloalkyl and heterocycle;

R⁵ is a member selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl;

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen and alkyl, or R⁶ and R⁷ taken together with the atom to whichthey are attached form a ring selected from the group consisting ofcycloalkyl and heterocycle;

R⁸ is selected from the group consisting of hydrogen, alkyl, carboxy,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and —N(R²⁷R²⁸);

R⁹ and R¹⁰ are each independently selected from the group consisting ofhydrogen and alkyl, or R⁹ and R¹⁰ taken together with the atom to whichthey are attached form a ring selected from the group consisting ofcycloalkyl and heterocycle;

R¹¹ is selected from the group consisting of hydroxy and —N(R²⁹R³⁰);

R¹² is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl;

R¹³ and R¹⁴ are each independently selected from the group consisting ofhydrogen, alkyl, alkylsulfonyl, aryl, arylalkyl, aryloxyalkyl,arylsulfonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl,cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl,heteroarylsultonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyland heterocyclesulfonyl;

R¹⁵ is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl,heterocycle, heterocyclealkyl and heterocycleoxyalkyl;

R¹⁶ and R¹⁷ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, carboxycycloalkyl,cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl,heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl,heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,heterocyclesulfonyl, hydroxy, and -alkyl-C(O)N(R²⁰¹R²⁰²), or, R¹⁶ andR¹⁷ taken together with the atom to which they are attached form aheterocycle;

R²⁰¹ and R²⁰² are independently selected from the group consisting ofhydrogen and alkyl;

R¹⁸, R¹⁹ and R²⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl,carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heterocycle and heterocyclealkyl;

R²¹ and R²² are each independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl,arylsulfonyl, cycloalkyl, carboxyalkyl, carboxycycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl,heteroarylsulfonyl, heterocycle, heterocyclecarbonyl andheterocyclesulfonyl;

R²³ and R²⁴ are each independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkoxy, alkylsulfonyl, aryl,arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl,cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl,heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl,heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyland hydroxy, or, R²³ and R²⁴ taken together with the atom to which theyare attached form a ring selected from the group consisting ofheteroaryl and heterocycle;

R²⁵ and R²⁶ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, carboxycycloalkyl,cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl,heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl,heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,heterocyclesulfonyl, and hydroxy, or, R²⁵ and R²⁶ taken together withthe atom to which they are attached form a heterocycle;

R²⁷ and R²⁸ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl,cycloalkyloxy, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heteroarylsulfonyl,heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl,heterocyclesulfonyl and hydroxy, or, R²⁷ and R²⁸ taken together with theatom to which they are attached form a heterocycle; and

R²⁹ and R³⁰ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl,cycloalkyloxy, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heteroarylsulfonyl,heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl,heterocyclesulfonyl, and hydroxy, or, R²⁹ and R³⁰ taken together withthe atom to which they are attached form a heterocycle;

provided that, if R¹ is hydrogen; then at least one of A¹, A², A³ and A⁴is not hydrogen.

A further aspect of the present invention encompasses the use of thecompounds of formula (I) for the treatment of disorders that aremediated by 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme, such asnon-insulin dependent type 2 diabetes, insulin resistance, obesity,lipid disorders, metabolic syndrome and other diseases and conditionsthat are mediated by excessive glucocorticoid action, comprisingadministering a therapeutically effective amount of a compound offormula (I).

According to still another aspect, the present invention is directed toa pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) in combination with apharmaceutically suitable carrier.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the results of memory consolidation in treated anduntreated mice measured as Mean Transfer Latency.

FIG. 2 depicts amount of phosphorylation of CREB in treated anduntreated mice.

FIG. 3 shows the results of memory consolidation in treated anduntreated mice measured as Mean Transfer Latency.

FIG. 4 shows the results of short memory retention in treated anduntreated mice measured as Mean Transfer Latency.

FIGS. 5 a-5 c show REM episodes, time and latency to first episode,respectively, on rat treated with an exemplary 11β-HSD-1 inhibitor.

FIGS. 6 a, 6 b and 6 c show the effects of an exemplary 11β-HSD-1inhibitor on cortical and hippocampal Ach release.

FIGS. 7 a and 7 b show the effects of an exemplary 1β-HSD-1 inhibitor oncortical and hippocampal 5-HT release.

DETAILED DESCRIPTION OF THE INVENTION

All patents, patent applications and literature references cited in thespecification are herein incorporated by reference in their entirety.

One aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen; and A¹, R³, R⁴, D and E are as described in thesummary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ are hydrogen; and A¹, D and E are as described in the summaryof the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ are hydrogen;

D is —O—; and A¹ and E are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ are hydrogen;

D is —O—;

E is as described in the summary of the invention; and

A¹ is selected from the group consisting of A¹ is selected from thegroup consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl,heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl, —S(O)-alkyl,—C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷), —C(R^(18a)R^(19a))—C(O)N(R²³R²⁴),—C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶), —CO₂R¹⁵,—C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴) whereinR¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³, R²⁴, R²⁵,and R²⁶ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ are hydrogen;

D is —O—;

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention; and

E is selected from the group consisting of aryl, cycloalkyl, heteroaryl,heterocycle, arylalkyl and cycloalkylalkyl.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ is hydrogen;

R⁴ is alkyl; and A¹, D and E are as described in the summary of theinvention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ is hydrogen;

R⁴ is alkyl;

D is —O—; and A¹ and E are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ is hydrogen;

R⁴ is alkyl;

D is —O—;

E is as described in the summary of the invention; and

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R¹⁸R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶), —CO₂R¹⁵,—C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴) whereinR¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³, R²⁴, R²⁵,and R²⁶ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ is hydrogen;

R⁴ is alkyl;

D is —O—;

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention; and

E is selected from the group consisting of aryl, cycloalkyl, heteroaryl,heterocycle, arylalkyl and cycloalkylalkyl.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ are alkyl; and A¹, D and E are as described in the summary ofthe invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ are alkyl;

D is —O—; and A¹ and E are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ are alkyl;

D is —O—;

E is as described in the summary of the invention; and

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ are alkyl;

D is —O—;

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention; and

E is selected from the group consisting of aryl, cycloalkyl, heteroaryl,heterocycle, arylalkyl and cycloalkylalkyl.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma ring selected from the group consisting of cycloalkyl and heterocycle;and A¹, D and E are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma cycloalkyl ring; and A¹, D and E are as described in the summary ofthe invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma cycloalkyl ring;

D is —O—; and A¹ and E are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma cycloalkyl ring;

D is —O—;

E is as described in the summary of the invention; and

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma cycloalkyl ring;

D is —O—;

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(9a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention; and

E is selected from the group consisting of aryl, cycloalkyl, heteroaryl,heterocycle, arylalkyl and cycloalkylalkyl.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma cyclopropyl ring;

D is —O—;

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention; and

E is selected from the group consisting of aryl, cycloalkyl, heteroaryl,heterocycle, arylalkyl and cycloalkylalkyl.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma cyclobutyl ring;

D is —O—;

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention; and

E is selected from the group consisting of aryl, cycloalkyl, heteroaryl,heterocycle, arylalkyl and cycloalkylalkyl.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen; and

R³ and R⁴ taken together with the atoms to which they are attached forma heterocycle, and A¹, D and E are as described in the summary of theinvention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma heterocycle;

D is —O—; and A¹ and E are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma heterocycle;

E is as described in the summary of the invention;

D is —O—; and

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ and R⁴ taken together with the atoms to which they are attached forma heterocycle;

D is —O—;

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention; and

E is selected from the group consisting of aryl, cycloalkyl, heteroaryl,heterocycle, arylalkyl and cycloalkylalkyl.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R⁴ and E taken together with the atoms to which they are attached form aheterocycle; and A¹ and D are as described in the summary of theinvention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R⁴ and E taken together with the atoms to which they are attached form aheterocycle;

D is —O— and A¹ is as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R⁴ and E taken together with the atoms to which they are attached form aheterocycle;

D is —O—; and

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR¹², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein A¹ is selected from the group consisting ofalkylsulfonyl, arylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl andheterocyclesulfonyl;

A², A³ and A⁴ are hydrogen;

D is —O—; and R¹, R², R³, R⁴, and E are as described in the summary ofthe invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein A¹ is —S(O)₂—N(R²⁵R²⁶) wherein R²⁵ and R²⁶ are asdescribed in the summary of the invention;

A², A³ and A⁴ are hydrogen;

D is —O—; and R¹, R², R³, R⁴, and E are as described in the summary ofthe invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein A¹ is —C(O)—N(R¹⁶R¹⁷) wherein R¹⁶ is selected fromthe group consisting of hydrogen and alkyl and R¹⁷ is selected from thegroup consisting of arylalkyl and heteroarylalkyl;

D is —O—;

A², A³ and A⁴ are hydrogen; and R¹, R², R³, R⁴, and E are as describedin the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —S—, —S(O)— and —S(O)₂; and

A¹ is selected from the group consisting of alkenyl, alkylsulfonyl,cyano, heteroaryl, heteroarylalkyl, —OR², carboxyalkyl, —S-alkyl,—S(O)-alkyl, —C(R¹⁸R¹⁹)—OR²⁰, —C(O)—N(R¹⁶R¹⁷),—C(R^(18a)R^(19a))—C(O)N(R²³R²⁴), —C(═NOH)—N(H)₂, —S(O)₂—N(R²⁵R²⁶),—CO₂R¹⁵, —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶), and —C(R²¹R²²)—N(R²³R²⁴)wherein R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^(18a), R^(19a), R²¹, R²², R²³,R²⁴, R²⁵, and R²⁶ are as described in the summary of the invention;

E is selected from the group consisting of aryl, cycloalkyl, heteroaryl,heterocycle, arylalkyl and cycloalkylalkyl; and

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, alkyl and arylalkyl, or R³ and R⁴ together with the atom towhich they are attached form a cycloalkyl ring.

Another aspect of the present invention is directed to a compoundselected from the following group

-   E-4-[(2-methyl-2-phenoxypropanoyl)amino]adamantane-1-carboxamide;-   E-4-[(2-methyl-2-{[4-(trifluoromethyl)benzyl]oxy}propanoyl)amino]adamantane-1-carboxamide;-   E-({2-methyl-2-[(2-methylcyclohexyl)oxy]propanoyl}amino)adamantane-1-carboxylic    acid;-   E-4-({2-methyl-2-[(3-methylcyclohexyl)oxy]propanoyl}amino)adamantane-1-carboxylic    acid;-   E-4-{[2-(cycloheptyloxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-(cyclohexylmethoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxylic    acid;-   E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-({2-methyl-2-[(4-methylcyclohexyl)oxy]propanoyl}amino)adamantane-1-carboxamide;-   E-4-[(2-phenoxypropanoyl)amino]adamantane-1-carboxamide;-   E-4-{[2-methyl-2-(2-methylphenoxy)propanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-methyl-2-(4-methylphenoxy)propanoyl]amino)}adamantane-1-carboxylic    acid;-   E-4-{[2-(2-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-(2-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-{[2-(4-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-({2-methyl-2-[3-(trifluoromethyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;-   E-4-{[2-(3-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-2-(4-Chloro-phenoxy)-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide;-   E-{[2-Methyl-2-(4-methylphenoxy)propanoyl]amino)}adamantane-1-carboxamide;-   E-4-{[2-(3-Chlorophenoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxamide;-   E-4-((2-Methyl-2-[4-(trifluoromethoxy)phenoxy]propanoyl)amino)adamantane-1-carboxamide;-   E-4-{[2-(3-Bromophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   4-({[((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)carbonyl]amino)}methyl)benzoic    acid;-   E-4-{[2-(2,3-Dimethylphenoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxylic    acid;-   tert-Butyl    4-(2-{[(E)-5-(aminocarbonyl)-2-adamantyl]amino)}-1,1-dimethyl-2-oxoethoxy)phenylcarbamate;-   E-N-[4-(Aminocarbonyl)benzyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-N-[4-(Aminocarbonyl)methyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   3-({[((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)carbonyl]amino}methyl)benzoic    acid;-   E-4-({2-[(5-Bromopyridin-2-yl)oxy]-2-methylpropanoyl}amino)adamantane-1-carboxamide;-   E-4-{[2-(2-Cyanophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-{[2-(4-Hydroxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   ((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino})-1-adamantyl)acetic    acid;-   N-[(E)-5-(2-Amino-2-oxoethyl)-2-adamantyl]-2-(4-chlorophenoxy)-2-methylpropanamide;-   2-(4-Chlorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-ylmethyl)-2-adamantyl]propanamide;-   N-{(E)-5-[(Aminosulfonyl)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide;-   N-{(E)-5-[(Z)-Amino(hydroxyimino)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide;-   E-N-[4-(Aminosulfonyl)benzyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-N-(4-{[(methylsulfonyl)amino]carbonyl}benzyl)adamantane-1-carboxamide;-   E-4-({2-[(4-Chlorophenyl)thio]-2-methylpropanoyl}amino)adamantane-1-carboxylic    acid;-   E-4-({2-[(4-Methoxyphenyl)thio]-2-methylpropanoyl}amino)adamantane-1-carboxamide    amide;-   E-4-({2-[(4-Methoxyphenyl)sulfinyl]-2-methylpropanoyl}amino)adamantane-1-carboxamide;-   E-4-({2-[(4-Methoxyphenyl)sulfonyl]-2-methylpropanoyl}amino)adamantane-1-carboxamide;-   E-4-({2-[4-Chloro-2-(pyrrolidin-1-ylsulfonyl)phenoxy]-2-methylpropanoyl)}amino)adamantane-1-carboxamide;-   E-4-({2-Methyl-2-[4-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;-   E-4-({2-Methyl-2-[2-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;-   E-4-[(2-{4-Chloro-2-[(diethylamino)sulfonyl]phenoxy)-2-methylpropanoyl)amino]adamantane-1-carboxamide;-   E-4-((2-Methyl-2-[4-(pyrrolidin-1-ylsulfonyl)phenoxy]propanoyl)}amino)adamantane-1-carboxamide;-   2-(2-Chloro-4-fluorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamide;-   2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2-adamantyl]propanamide;-   2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylthio)-2-adamantyl]propanamide;-   2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methyl    sulfonyl)-2-adamantyl]propanamide;-   2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylsulfinyl)-2-adamantyl]propanamide;-   N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-2-methylpropanamide;-   E-4-({[1-(4-Chlorophenoxy)cyclobutyl]carbonyl}amino)adamantane-1-carboxamide;-   4-[({[((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)methyl]sulfonyl}amino)methyl]benzoic    acid;-   2-(4-Chlorophenoxy)-N-[(E)-5-(1H-imidazol-2-yl)-2-adamantyl]-2-methylpropanamide;-   (2E)-3-((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)acrylic    acid;-   (E)-4-[(2-Methyl-2-j{[5-(1H-pyrazol-1-yl)pyridin-2-yl]oxy}propanoyl)amino]adamantane-1-carboxamide;-   2-(4-Chlorophenoxy)-N-[(E)-5-isoxazol-5-yl-2-adamantyl]-2-methylpropanamide;-   2-(4-Chlorophenoxy)-2-methyl-N-{(E)-5-[(2-morpholin-4-ylethoxy)methyl]-2-adamantyl}propanamide;-   N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chlorophenoxy)-2-methylpropanamide;-   N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-(2-methylphenoxy)propanamide;-   N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-(4-methylphenoxy)propanamide;-   N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethyl)phenoxy]propanamide;-   N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethoxy)phenoxy]propanamide;-   N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chloro-4-fluorophenoxy)-2-methylpropanamide;-   E-4-{[2-(2-chlorophenoxy)-2-methyl-3-phenylpropanoyl]amino)}adamantane-1-carboxamide;-   2-(4-chlorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamide;-   E-({2-methyl-2-[(5-morpholin-4-ylpyridin-2-yl)oxy]propanoyl}amino)adamantane-1-carboxamide;-   E-4-{[2-methyl-2-(pyridin-2-yloxy)propanoyl]amino}adamantane-1-carboxamide;-   2-(4-chlorophenoxy)-2-methyl-N-{E)-5-[(methylamino)sulfonyl]-2-adamantyl}propanamide;-   3-((E)-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)propanoic    acid;-   2-(4-chlorophenoxy)-N-{(E)-5-[(dimethylamino)sulfonyl]-2-adamantyl)}-2-methylpropanamide;-   E-4-[(2-{[5-(1H-imidazol-1-yl)pyridin-2-yl]oxy}-2-methylpropanoyl)amino]adamantane-1-carboxamide;-   2-(4-chlorophenoxy)-2-methyl-N-[(E)-5-(1H-pyrazol-3-yl)-2-adamantyl]propanamide;-   N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(3-chlorophenoxy)-2-methylpropanamide;-   N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-methyl-2-(3-methylphenoxy)propanamide;-   N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(2-methoxyphenoxy)-2-methylpropanamide;-   N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(3-methoxyphenoxy)-2-methylpropanamide;-   N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-methoxyphenoxy)-2-methylpropanamide;-   N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-cyanophenoxy)-2-methylpropanamide;-   E-4-{[2-methyl-2-(2-methylphenoxy)propanoyl]amino)}adamantane-1-carboxamide;-   E-4-{[2-methyl-2-(3-methylphenoxy)propanoyl]amino)}adamantane-1-carboxamide;-   E-4-[(2-methyl-2-{[(1S,2S)-2-methylcyclohexyl]oxy}propanoyl)amino]adamantane-1-carboxylic    acid;-   E-4-({2-methyl-2-[(2-methylcyclohexyl)oxy]propanoyl}amino)adamantane-1-carboxamide-   E-4-{[2-(cycloheptyloxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-{[2-(cyclohexylmethoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-({2-methyl-2-[(3-methylcyclohexyl)oxy]propanoyl)}amino)adamantane-1-carboxamide;-   E-4-{[2-(2-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   4-{[({(E)-4-[(2-methyl-2-phenoxypropanoyl)amino]-1-adamantyl)}carbonyl)amino]methyl)}benzoic    acid;-   E-4-({2-[(4,4-dimethylcyclohexyl)oxy]-2-methylpropanoyl}amino)adamantane-1-carboxylic    acid;-   E-4-{[2-methyl-2-(1,2,3,4-tetrahydronaphthalen-2-yloxy)propanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-(4-bromophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-methyl-2-(1-naphthyloxy)propanoyl]amino}adamantane-1-carboxylic    acid;-   E-{[2-(2,3-dichlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-(2,4-dichlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-(2,5-dichlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-(2,4-dimethylphenoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxylic    acid;-   E-4-{[2-(2,5-dimethylphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-methyl-2-(2-naphthyloxy)propanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-(4-bromo-2-fluorophenoxy)-2-methylpropanoyl]amino)adamantane-1-carboxylic    acid;-   E-4-((2-methyl-2-[(7-methyl-2,3-dihydro-1H-inden-4-yl)oxy]propanoyl}amino)adamantane-1-carboxylic    acid;-   E-4-{[2-(4-bromo-2-chlorophenoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxylic    acid;-   E-4-{[2-(1,1-biphenyl-3-yloxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-(2-bromophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   E-N-[4-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenoxypropanoyl)amino]adamantane-1-carboxamide;-   E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-N-(1,3-thiazol-5-ylmethyl)adamantane-1-carboxamide;-   E-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino)}-N-(pyridin-4-ylmethyl)adamantane-1-carboxamide;-   E-4-{[2-(4-aminophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-({2-methyl-2-[2-(trifluoromethoxy)phenoxy]propanoyl}amino)adamantane-1-carboxamide;-   E-4-({2-methyl-2-[2-(trifluoromethyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;-   E-4-({2-methyl-2-[4-(pyrrolidin-1-ylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;-   2-(2-chloro-4-fluorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamide;-   2-(2-chloro-4-fluorophenoxy)-N-[(E)-5-cyano-2-adamantyl]-2-methylpropanamide;-   E-4-[(2-methyl-2-(4-[(trifluoroacetyl)amino]phenoxy)propanoyl)amino]adamantane-1-carboxamide;-   E-{[2-(3-bromo-4-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-{[2-(2,5-dibromo-4-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-{[2-(2-bromo-4-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-{[2-(2-chloro-4-fluorophenoxy)-2-methylpropanoyl]amino}-N,N-dimethyladamantane-1-carboxamide;-   2-(4-chlorophenoxy)-N-((E)-5-{[(4-methoxy-6-methylpyrimidin-2-yl)amino]methyl}-2-adamantyl)-2-methylpropanamide;-   E-4-{[2-(4-{[(tert-butylamino)carbonyl]amino}phenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   ethyl    4-(2-{[(E)-5-(aminocarbonyl)-2-adamantyl]amino}-1,1-dimethyl-2-oxoethoxy)phenylcarbamate;-   E-4-[(2-methyl-2-{4-[(propylsulfonyl)amino]phenoxy}propanoyl)amino]adamantane-1-carboxamide;-   E-4-[(2-{4-[(3,3-dimethylbutanoyl)amino]phenoxy}-2-methylpropanoyl)amino]adamantane-1-carboxamide;-   E-4-{[2-methyl-2-(phenylsulfinyl)propanoyl]amino}adamantane-1-carboxylic    acid;-   E-4-{[2-methyl-2-(phenylsulfonyl)propanoyl]amino}adamantane-1-carboxylic    acid;-   N-[(E)-5-cyano-2-adamantyl]-2-[(4-methoxyphenyl)sulfonyl]-2-methylpropanamide;-   2-[(4-methoxyphenyl)sulfonyl]-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2-adamantyl]propanamide;    and-   E-4-({2-[4-(benzyloxy)phenoxy]-2-methylpropanoyl}amino)adamantane-1-carboxamide.

Another embodiment of the present invention discloses a method ofinhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme,comprising administering to a mammal, a therapeutically effective amountof the compound of formula (I).

Another embodiment of the present invention discloses a method oftreating disorders in a mammal by inhibiting 11-beta-hydroxysteroiddehydrogenase Type I enzyme, comprising administering to a mammal, atherapeutically effective amount of the compound of formula (I).

Another embodiment of the present invention discloses a method oftreating non-insulin dependent type 2 diabetes in a mammal by inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme comprisingadministering to a mammal, a therapeutically effective amount of thecompound of formula (I).

Another embodiment of the present invention discloses a method oftreating insulin resistance in a mammal by inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme comprisingadministering to a mammal, a therapeutically effective amount of thecompound of formula (I).

Another embodiment of the present invention discloses a method oftreating obesity in a mammal by inhibiting 11-beta-hydroxysteroiddehydrogenase Type I enzyme comprising administering to a mammal, atherapeutically effective amount of the compound of formula (I).

Another embodiment of the present invention discloses a method oftreating lipid disorders in a mammal by inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme comprisingadministering to a mammal, a therapeutically effective amount of thecompound of formula (I).

Another embodiment of the present invention discloses a method oftreating metabolic syndrome in a mammal by inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme comprisingadministering to a mammal, a therapeutically effective amount of thecompound of formula (I).

Another embodiment of the present invention discloses a method oftreating diseases and conditions that are mediated by excessiveglucocorticoid action in a mammal by inhibiting 11-beta-hydroxysteroiddehydrogenase Type I enzyme comprising administering to a mammal, atherapeutically effective amount of the compound of formula (I).

Another embodiment of the present invention discloses a pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound of formula (I) in combination with a pharmaceutically suitablecarrier.

DEFINITION OF TERMS

The term “alkenyl” as used herein, refers to a straight or branchedchain hydrocarbon containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.Alkenyls of the present invention can be unsubstituted or substitutedwith one substituent selected from the group consisting of carboxy,alkoxycarbonyl and aryloxycarbonyl.

The term “alkoxy” as used herein, refers to an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy andhexyloxy.

The term “alkoxyalkyl” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl and methoxymethyl.

The term “alkoxycarbonyl” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl and tert-butoxycarbonyl.

The term “alkyl” as used herein, refers to a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl andn-decyl.

The term “alkylcarbonyl” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.

The term “alkylsulfonyl” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkyl-NH” as used herein, refers to an alkyl group, as definedherein, appended to the parent molecular moiety through a nitrogen atom.

The term “alkyl-NH-alkyl” as used herein, refers to an alkyl-NH group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein.

The term “aryl” as used herein, means a phenyl group, or a bicyclic or atricyclic fused ring system. Bicyclic fused ring systems are exemplifiedby a phenyl group appended to the parent molecular moiety and fused to acycloalkyl group, as defined herein, a phenyl group, a heteroaryl group,as defined herein, or a heterocycle, as defined herein. Tricyclic fusedring systems are exemplified by an aryl bicyclic fused ring system, asdefined herein and fused to a cycloalkyl group, as defined herein, aphenyl group, a heteroaryl group, as defined herein, or a heterocycle,as defined herein. Representative examples of aryl include, but are notlimited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl,naphthyl, phenyl and tetrahydronaphthyl.

The aryl groups of this invention may be optionally substituted with 1,2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylsulfonyl, alkynyl, aryl, arylalkoxy, arylcarbonyl,aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclecarbonyl,heterocycleoxy, heterocyclesulfonyl, hydroxy, hydroxyalkyl, nitro,R_(f)R_(g)N—, R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl,—N(H)C(O)N(H)(alkyl), and R_(f)R_(g)Nsulfonyl, wherein R_(f) and R_(g)are independently selected from the group consisting of hydrogen, alkyl,alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,haloalkyl, haloalkylcarbonyl and cycloalkylalkyl wherein the cycloalkyl,the cycloalkyl of cycloalkylalkyl as represented by R_(f) and R_(g) areeach independently unsubstituted or substituted with 1, 2 or 3substituents independently selected from the group consisting ofhalogen, alkyl and haloalkyl. The substituent aryl, the aryl ofarylalkoxy, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl ofarylsulfonyl, the substituent heteroaryl, the heteroaryl ofheteroarylalkyl, the heteroaryl of heteroarylcarbonyl, the substituentheterocycle, the heterocycle of heterocyclecarbonyl, the heterocycle ofheterocycleoxy, the heterocycle of heterocyclesulfonyl may be optionallysubstituted with 1, 2 or 3 substituents independently selected from thegroup consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl,halogen, hydroxy, hydroxyalkyl, nitro, R_(f)R^(g)N—, R_(f)R_(g)Nalkyl,R_(f)R_(g)Ncarbonyl and R_(f)R_(g)Nsulfonyl wherein R_(f) and R_(g) areas described herein.

The term “arylalkyl” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl and2-naphth-2-ylethyl.

The term “arylcarbonyl” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofarylcarbonyl include, but are not limited to, benzoyl and naphthoyl.

The term “aryl-NH-” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through a nitrogen atom.

The term “aryl-NH-alkyl” as used herein, refers to an aryl-NH— group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “arylalkoxy” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through analkoxy moiety, as defined herein.

The term “aryloxy” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through an oxy moiety,as defined herein.

Representative examples of aryloxy include, but are not limited tophenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxyand 3,5-dimethoxyphenoxy.

The term “aryloxyalkyl” as used herein, refers to an aryloxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “aryloxycarbonyl” as used herein, refers to an aryloxy group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein.

The term “arylsulfonyl” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein.

Representative examples of arylsulfonyl include, but are not limited to,phenylsulfonyl, 4-bromophenylsulfonyl and naphthylsulfonyl.

The term “carbonyl” as used herein refers to a —C(O)— group.

The term “carboxy” as used herein refers to a —C(O)—OH group.

The term “carboxyalkyl” as used herein refers to a carboxy group asdefined herein, appended to the parent molecular moiety through an alkylgroup as defined herein.

The term “carboxycycloalkyl” as used herein refers to a carboxy group asdefined herein, appended to the parent molecular moiety through ancycloalkyl group as defined herein.

The term “cycloalkyl” as used herein, refers to a monocyclic, bicyclic,or tricyclic ring system. Monocyclic ring systems are exemplified by asaturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms.Examples of monocyclic ring systems include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic fused ringsystems are exemplified by a cycloalkyl group appended to the parentmolecular moiety and fused to a cycloalkyl group, as defined herein, aphenyl group, a heteroaryl group, as defined herein, or a heterocycle,as defined herein. Tricyclic fused ring systems are exemplified by acycloalkyl bicyclic fused ring system, as defined herein and fused to acycloalkyl group, as defined herein, a phenyl group, a heteroaryl group,as defined herein, or a hetrocycle, as defined herein. Bicyclic ringsystems are also exemplified by a bridged monocyclic ring system inwhich two non-adjacent carbon atoms of the monocyclic ring are linked byan alkylene bridge of between one and three additional carbon atoms.Representative examples of bicyclic ring systems include, but are notlimited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane andbicyclo[4.2.1]nonane. Tricyclic ring systems are also exemplified by abicyclic ring system in which two non-adjacent carbon atoms of thebicyclic ring are linked by a bond or an alkylene bridge of between oneand three carbon atoms. Representative examples of tricyclic-ringsystems include, but are not limited to, tricyclo[3.3.1.0^(3,7)]nonaneand tricyclo[3.3.1.1^(3,7)]decane (adamantane).

The cycloalkyl groups of this invention may be substituted with 1, 2, 3,4 or 5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy,arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl,ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro,R_(f)R_(g)N—, R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl andR_(f)R_(g)Nsulfonyl, wherein R_(f) and R_(g) are independently selectedfrom the group consisting of hydrogen, alkyl, alkoxyalkyl,alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, haloalkyl,haloalkylcarbonyl and cycloalkylalkyl wherein the cycloalkyl, thecycloalkyl of cycloalkylalkyl as represented by R_(f) and R_(g) are eachindependently unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, alkyl andhaloalkyl. The substituent aryl, the aryl of arylalkyl, the aryl ofarylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, thesubstituent heteroaryl, the heteroaryl of heteroarylalkyl, theheteroaryl of heteroarylcarbonyl, the substituent heterocycle, theheterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl,the heterocycle of heterocycleoxy, the heterocycle ofheterocyclesulfonyl may be optionally substituted with 0, 1, 2 or 3substituents independently selected from the group consisting of alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy,carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,R_(f)R_(g)N—, R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl andR_(f)R_(g)Nsulfonyl wherein R_(f) and R_(g) are as described herein.

The term “cycloalkylalkyl” as used herein, refers to a cycloalkyl group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples ofcycloalkylalkyl include, but are not limited to, cyclopropylmethyl,2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and4-cycloheptylbutyl.

The term “cycloalkylcarbonyl” as used herein, refers to cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,2-cyclobutylcarbonyl and cyclohexylcarbonyl.

The term “cycloalkyloxy” as used herein, refers to cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an oxygroup, as defined herein.

The term “cycloalkylsulfonyl” as used herein, refers to cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples ofcycloalkylsulfonyl include, but are not limited to, cyclohexylsulfonyland cyclobutylsulfonyl.

The term “halo” or “halogen” as used herein, refers to —Cl, —Br, —I or—F.

The term “haloalkyl” as used herein, refers to at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl and 2-chloro-3-fluoropentyl.

The term “haloalkylcarbonyl” as used herein, refers to a haloalkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein.

The term “heteroaryl” as used herein, refers to an aromatic monocyclicring or an aromatic bicyclic ring system. The aromatic monocyclic ringsare five or six membered rings containing at least one heteroatomindependently selected from the group consisting of N, O and S. The fivemembered aromatic monocyclic rings have two double bonds and the sixmembered aromatic monocyclic rings have three double bonds. The bicyclicheteroaryl groups are exemplified by a monocyclic heteroaryl ringappended to the parent molecular moiety and fused to a monocycliccycloalkyl group, as defined herein, a monocyclic aryl group, as definedherein, a monocyclic heteroaryl group, as defined herein, or amonocyclic heterocycle, as defined herein. Representative examples ofheteroaryl include, but are not limited to, benzimidazolyl,benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl,imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuranyl,isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,oxadiazolyl, oxazolyl, phthalazinyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, quinolizinyl,quinoxalinyl, quinazolinyl, tetrazolyl, thiadiazolyl, thiazolyl,thienyl, triazolyl and triazinyl.

The term “heteroarylalkyl” as used herein, refers to a heteroaryl, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The heteroaryls of this invention may be optionally substituted with 1,2 or 3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy,arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl,ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl,heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,heterocycleoxy, hydroxy, hydroxyalkyl, nitro, R_(f)R_(g)N—,R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl and R_(f)R_(g)Nsulfonyl, whereinR_(f) and R_(g) are independently selected from the group consisting ofhydrogen, alkyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl,alkylsulfonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl andcycloalkylalkyl wherein the cycloalkyl, the cycloalkyl ofcycloalkylalkyl as represented by R_(f) and R_(g) are each independentlyunsubstituted or substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of halogen, alkyl and haloalkyl. Thesubstituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, thearyl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl,the heteroaryl of heteroarylalkyl, the substituent heterocycle, theheterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl,the heterocycle of heterocycleoxy may be optionally substituted with 1,2 or 3 substituents independently selected from the group consisting ofalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl,carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl,nitro, R_(f)R_(g)N—, R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl andR_(f)R_(g)Nsulfonyl wherein R_(f) and R_(g) are as described above.

The term “heterocycle” as used herein, refers to a non-aromaticmonocyclic ring or a non-aromatic bicyclic ring. The non-aromaticmonocyclic ring is a three, four, five, six, seven, or eight memberedring containing at least one heteroatom, independently selected from thegroup consisting of N, O and S. Representative examples of monocyclicring systems include, but are not limited to, azetidinyl, aziridinyl,diazepinyl, dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrothienyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone) and thiopyranyl. The bicyclic heterocycles areexemplified by a monocyclic heterocycle appended to the parent molecularmoiety and fused to a monocyclic cycloalkyl group, as defined herein, amonocyclic aryl group, a monocyclic heteroaryl group, as defined herein,or a monocyclic heterocycle, as defined herein. Bicyclic ring systemsare also exemplified by a bridged monocyclic ring system in which twonon-adjacent atoms of the monocyclic ring are linked by a bridge ofbetween one and three additional atoms selected from the groupconsisting of carbon, nitrogen and oxygen. Representative examples ofbicyclic ring systems include but are not limited to, for example,benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl,cinnolinyl, 1,5-diazocanyl, 3,9-diaza-bicyclo[4.2.1]non-9-yl,3,7-diazabicyclo[3.3.1]nonane, octahydro-pyrrolo[3,4-c]pyrrole,indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-1H-benzo[c]azepine,2,3,4,5-tetrahydro-1H-benzo[b]azepine,2,3,4,5-tetrahydro-1H-benzo[d]azepine, tetrahydroisoquinolinyl andtetrahydroquinolinyl.

The heterocycles of this invention may be optionally substituted with 1,2 or 3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy,arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy,formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl,heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy,hydroxy, hydroxyalkyl, nitro, R_(f)R_(g)N—, R_(f)R_(g)Nalkyl,R_(f)R_(g)Ncarbonyl and R_(f)R_(g)Nsulfonyl, wherein R_(f) and R_(g) areindependently selected from the group consisting of hydrogen, alkyl,alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,haloalkyl, haloalkylcarbonyl and cycloalkylalkyl wherein the cycloalkyl,the cycloalkyl of cycloalkylalkyl as represented by R_(f) and R_(g) areeach independently unsubstituted or substituted with 1, 2 or 3substituents independently selected from the group consisting ofhalogen, alkyl and haloalkyl. The substituent aryl, the aryl ofarylalkyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl ofarylsulfonyl, the heteroaryl, the heteroaryl of heteroarylalkyl, thesubstituent heterocycle, the heterocycle of heterocyclealkyl, theheterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy,may be optionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl,cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, R_(f)R_(g)N—,R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl and R_(f)R_(g)Nsulfonyl whereinR_(f) and R^(g) are as described herein.

The term “heterocyclealkyl” as used herein, refers to a heterocycle, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heterocyclealkylinclude, but are not limited to, pyridin-3-ylmethyl and2-pyrimidin-2-ylpropyl.

The term “heterocyclealkoxy” as used herein, refers to a heterocycle, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein.

The term “heterocycleoxy” as used herein, refers to a heterocycle, asdefined herein, appended to the parent molecular moiety through an oxygroup, as defined herein.

The term “heterocycleoxyalkyl” as used herein, refers to aheterocycleoxy, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein.

The term “heterocycle-NH-” as used herein, refers to a heterocycle, asdefined herein, appended to the parent molecular moiety through anitrogen atom.

The term “heterocycle-NH-alkyl” as used herein, refers to aheterocycle-NH—, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein.

The term “heterocyclecarbonyl” as used herein, refers to a heterocycle,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofheterocyclecarbonyl include, but are not limited to,1-piperidinylcarbonyl, 4-morpholinylcarbonyl, pyridin-3-ylcarbonyl andquinolin-3-ylcarbonyl.

The term “heterocyclesulfonyl” as used herein, refers to a heterocycle,as defined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofheterocyclesulfonyl include, but are not limited to,1-piperidinylsulfonyl, 4-morpholinylsulfonyl, pyridin-3-ylsulfonyl andquinolin-3-ylsulfonyl.

The term “hydroxy” as used herein, refers to an —OH group.

The term “hydroxyalkyl” as used herein, refers to a hydroxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of hydroxyalkylinclude, but are not limited to, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl and 2-ethyl-4-hydroxyheptyl.

The term “oxo” as used herein, refers to a ═O group.

The term “oxy” as used herein, refers to a —O— group.

The term “sulfonyl” as used herein, refers to a —S(O)₂— group.

Salts

The present compounds may exist as therapeutically suitable salts. Theterm “therapeutically suitable salt,” refers to salts or zwitterions ofthe compounds which are water or oil-soluble or dispersible, suitablefor treatment of disorders without undue toxicity, irritation andallergic response, commensurate with a reasonable benefit/risk ratio andeffective for their intended use. The salts may be prepared during thefinal isolation and purification of the compounds or separately byreacting an amino group of the compounds with a suitable acid. Forexample, a compound may be dissolved in a suitable solvent, such as butnot limited to methanol and water and treated with at least oneequivalent of an acid, like hydrochloric acid. The resulting salt mayprecipitate out and be isolated by filtration and dried under reducedpressure. Alternatively, the solvent and excess acid may be removedunder reduced pressure to provide the salt. Representative salts includeacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate,naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,glutamate, para-toluenesulfonate, undecanoate, hydrochloric,hydrobromic, sulfuric, phosphoric and the like. The amino groups of thecompounds may also be quaternized with alkyl chlorides, bromides andiodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl,myristyl, stearyl and the like.

Basic addition salts may be prepared during the final isolation andpurification of the present compounds by reaction of a carboxyl groupwith a suitable base such as the hydroxide, carbonate, or bicarbonate ofa metal cation such as lithium, sodium, potassium, calcium, magnesium,or aluminum, or an organic primary, secondary, or tertiary amine.Quaternary amine salts derived from methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine,pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine and N,N′-dibenzylethylenediamine, ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like, arecontemplated as being within the scope of the present invention.

Prodrugs

The present compounds may also exist as therapeutically suitableprodrugs. The term “therapeutically suitable prodrug,” refers to thoseprodrugs or zwitterions which are suitable for use in contact with thetissues of patients without undue toxicity, irritation and allergicresponse, are commensurate with a reasonable benefit/risk ratio and areeffective for their intended use. The term “prodrug,” refers tocompounds that are rapidly transformed in vivo to the parent compoundsof formula (I-IXc) for example, by hydrolysis in blood. The term“prodrug,” refers to compounds that contain, but are not limited to,substituents known as “therapeutically suitable esters.” The term“therapeutically suitable ester,” refers to alkoxycarbonyl groupsappended to the parent molecule on an available carbon atom. Morespecifically, a “therapeutically suitable ester,” refers toalkoxycarbonyl groups appended to the parent molecule on one or moreavailable aryl, cycloalkyl and/or heterocycle groups as defined herein.Compounds containing therapeutically suitable esters are an example, butare not intended to limit the scope of compounds considered to beprodrugs. Examples of prodrug ester groups include pivaloyloxymethyl,acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as othersuch groups known in the art. Other examples of prodrug ester groups arefound in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems,Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

Optical Isomers-Diastereomers-Geometric Isomers

Asymmetric centers may exist in the present compounds. Individualstereoisomers of the compounds are prepared by synthesis from chiralstarting materials or by preparation of racemic mixtures and separationby conversion to a mixture of diastereomers followed by separation orrecrystallization, chromatographic techniques, or direct separation ofthe enantiomers on chiral chromatographic columns. Starting materials ofparticular stereochemistry are either commercially available or are madeby the methods described hereinbelow and resolved by techniques wellknown in the art.

Geometric isomers may exist in the present compounds. The inventioncontemplates the various geometric isomers and mixtures thereofresulting from the disposal of substituents around a carbon-carbondouble bond, a cycloalkyl group, or a heterocycloalkyl group.

Substituents around a carbon-carbon double bond are designated as beingof Z or E configuration and substituents around a cycloalkyl orheterocycloalkyl are designated as being of cis or trans configuration.Furthermore, the invention contemplates the various isomers and mixturesthereof resulting from the disposal of substituents around an adamantanering system. Two substituents around a single ring within an adamantanering system are designated as being of Z or E relative configuration.For examples, sec C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. leNoble J. Org. Chem. 63: 2758-2760, 1998.

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes andExperimentals that illustrate a means by which the compounds of theinvention may be prepared.

The compounds of this invention may be prepared by a variety ofprocedures and synthetic routes. Representative procedures and syntheticroutes are shown in, but are not limited to, Schemes 1-18.

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: Cbz for benzyloxycarbonyl; CbzCl forbenzyloxycarbonyl chloride; DCE for 1,2-dichloroethane; DCM fordichloromethane; DMAP for dimethylaminopyridine; DME for 1,2-dimethoxyethane; DMF for N,N-dimethylformamide; DMSO for dimethylsulfoxide; DASTfor (diethylamino)sulfur trifluoride; DIPEA for Hünig's base fordiisopropylethylarnmine; DMPU for1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; EDCI for(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl; EtOAc for ethylacetate; Et₂O for diethyl ether, EtOH for ethanol; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate; HOBt for hydroxybenzotriazole hydrate; iPrOH forisopropyl alcohol; KOTMS for potassium trimethylsilanolate; LAH forlithium aluminum hydride; MeOH for methanol; NMO for N-methylmorpholineN-oxide; NaOAC for sodium acetate; OXONE for potassiumperoxymonosulfate; tBuOK for potassium tert-butoxide; TBTU forO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate; THFfor tetrahydrofuran; TosMIC for p-toluenesulfonylmethyl isocyanide; TPAPfor tetrapropylammonium perruthenate; TFAA for trifluoroaceticanhydride; tosyl for para-toluene sulfonyl, mesyl for methane sulfonyl,and triflate for trifluoromethane sulfonyl.

Acids of general formula (2) wherein X═OH can be coupled to substitutedadamantamines of general formula (I) with reagents such as EDCI and HOBtto provide amides of general formula (3). Substituted adamantanes ofgeneral formula (3), wherein A¹, A², A³, A⁴, R¹, R², R³, R⁴, D and E areas defined in formula I, may be prepared as in Scheme 1. Substitutedadamantamines of general formula (1), purchased or prepared usingmethodology known to those in the art, may be treated with acylatingagents of general formula (4), wherein X is chloro, bromo, or fluoro, Yis a leaving group such as Br (or a protected or masked leaving group)to provide amides of general formula (5). The substituted amides ofgeneral formula (5) may be treated with nucleophiles of general formula(6), wherein J is oxygen or sulfur and a base such as sodium hydride.When J is sulfur that reaction may be followed by oxidation withreagents like Oxone to provide amides of general formula (3) wherein Dcan become S(O) or S(O)₂. In some examples, A¹, A², A³ and/or A⁴ inamines of formula (1) may exist as a group further substituted with aprotecting group such as a carboxylic acid protected as the methylester. Examples containing a protected functional group may be requireddue to the synthetic schemes and the reactivity of said groups and couldbe later removed to provide the desired compound. Such protecting groupscan be removed using methodology known to those skilled in the art or asdescribed in T. W. Greene, P. G. M. Wuts “Protective Groups in OrganicSynthesis” 3^(rd) ed. 1999, Wiley & Sons, Inc.

Substituted adamantane amines of general formula (8), wherein A¹, A²,A³, A⁴, R¹ and R² are as defined in formula I, may be prepared as inScheme 2. Substituted adamantane ketones of general formula (7) can bepurchased or prepared using methodology known to those in the art.Ketones of general formula (7) can be treated with ammonia or primaryamines (R²NH₂) followed by reduction with reagents such as sodiumborohydride or H₂ over Pd/C in a solvent like methanol to provide aminesof general formula (8). In some examples, A¹, A², A³ and/or A⁴ inketones of formula (7) may be a functional group substituted with aprotecting group such as a carboxylic acid protected as the methylester. These protecting groups can be removed using methodology known tothose in the art in amines of general formula (8) or in compoundssubsequently prepared from ketones of general formula (7) or amines ofgeneral formula (8).

Substituted adamantanes of general formula (10), wherein A², A³ and A⁴are as defined in formula I, may be prepared as in Scheme 3. Substitutedadamantanes of general formula (9) can be purchased or prepared usingmethodology known to those skilled in the art. Adamantanes of generalformula (9) can be treated with oleum and formic acid followed by analcohol GOH, where G is an alkyl, cycloalkyl, hydrogen, aryl, or acidprotecting group, to provide adamantanes of general formula (10). Insome examples, G in formula (10) may be a protecting group such asmethyl. These protecting groups can be removed using methodology knownto those skilled in the art from adamantanes of general formula (10) orin compounds subsequently prepared from (10).

Substituted adamantanes of general formula (14), wherein A², A³, A⁴, R¹,R², R³, R⁴, D, E, R¹⁶ and R¹⁷ are as defined in formula I, may beprepared as in Scheme 4. Adamantyl acids of general formula (11) may beprepared as described herein or using methodology known to those skilledin the art. The acids of general formula (11) may be coupled with aminesof general formula (12), wherein R¹⁶ and R¹⁷ are defined as in formulaI, with reagents such asO-(benzotrialzol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU) to provide amides of general formula (13). In some examples, A²,A³, A⁴, R¹, R², R³, R¹⁶ and R¹⁷ in amines of formula (13) may contain afunctional group substituted with a protecting group, for example, acarboxy protected as an ester. These protecting groups may be removedusing methodology known to those in the art to provide amides of generalformula (14).

Acids of general formulas (17) wherein R³, R⁴, D and E are as defined informula (I) can be prepared as shown in Scheme 5.

Phenols and thiols of general formula (15) wherein D is —O— or —S—,purchased or prepared using methodology known to those skilled in theart, may be treated with a reagent like1,1,1-trichloro-2-methyl-propan-2-ol (16) in the presence of a base likesodium hydroxide in a solvent like acetone to provide acids of generalformula (17).

Esters of general formula (18) wherein P is an acid protecting groupsuch as, but not limited to, C₁-C₆ alkyl, aryl (substituted orunsubstituted) or arylalkyl (substituted or unsubstituted), may undergoan aromatic substitution or related reaction with halides of formulaE-X₁ wherein X₁ is Cl, Br or I and E is as defined in formula (I), inthe presence of a base like sodium hydride in a solvent like DMPU toafford compounds of formula (19). Removal of the acid protecting group,P, provides acids of formula (17). Cleavage of the acid protecting groupcan be conducted by either acidic or basic hydrolysis when P is C₁-C₆alkyl, or hydrogenolyis when P is benzyl.

Alternatively, esters of general formula (18) may be coupled withhalides of formula E-X₁ wherein X₁ is Cl, Br or I and E is aryl orheteroaryl, under with a metal catalyst like palladium along withligands, to provide compounds of formula (19).

Compounds of formula (19) can also be obtained from the reaction ofbromoesters of general formula (20), with compounds of formula (15)wherein D is —O— or —S— and E is defined as in formula (I), in thepresence of a base such as, but not limited to, potassium carbonate, toprovide esters of general formula (19).

Substituted adamantane amides of general formula (21), wherein R_(f) andR_(g) are independently selected from the group consisting of hydrogen,alkyl, alkoxyalkyl, alkylsulfonyl, cycloalkyl, and cycloalkylalkylwherein the cycloalkyl, the cycloalkyl of cycloalkylalkyl as representedby R_(f) and R_(g) are each independently unsubstituted or substitutedwith 1, 2 or 3 substituents independently selected from the groupconsisting of alkyl, halogen, and haloalkyl, Z is alkyl, aryl,heteroaryl, cycloalkyl, heterocycle, arylalkyl, heteroarylalkyl orheterocyclealkyl, and A², A³, A⁴, R¹, R², R³, R⁴, R¹⁸, R², D and E areas defined in formula (I), can be prepared as shown in Scheme 6.

Adamantane acids of general formula (20) can be coupled with amines offormula R_(f)R_(g)NH, in the presence of a coupling agent such as, butnot limited to, TBTU, and a base such as, but not limited, todiisopropylethylamine. The reaction is generally performed in a solventsuch as, but not limited to, DMF, at a temperature of about roomtemperature to about 50° C. to provide amides of general formula (21).

Substituted adamantanes of general formula (25), (26), and (27), whereinA², A³, A⁴, R¹, R², R³, R⁴, D and E are as defined in formula I, can beprepared as shown in Scheme 7.

Adamantanes of general formula (22) wherein P is hydrogen or an acidprotecting group such as, but not limited to, C₁-C₆ alkyl, aryl(substituted or unsubstituted) or arylalkyl (substituted orunsubstituted), can be converted to aldehydes of formula (23) by (a)treatment with a reducing agent such as, but not limited to, lithiumaluminum hydride, in a solvent like THF; and (b) treating the productfrom step (a) with an oxiding agent such as, but not limited to, TPAP,in the presence of NMO, and in a solvent like dichloroethane.

Adamantane aldehydes of general formula (23) can be treated with TosMICand a base like t-BuOK in a solvent mixture like DME and ethanol toprovide nitriles of general formula (24). Nitriles of general formula(24) can be hydrolyzed with potassium hydroxide in a solvent likeethylene glycol to provide acids of general formula (25). When treatedwith hydrogen peroxide and sodium hydroxide in a solvent mixture likemethanol and DMSO, nitriles of general formula (24) can be transformedto amides of formula (26).

Tetrazoles of formula (27) can be prepared from adamantanes of generalformula (24) when treated with reagents like sodium azide and zincbromide in a solvent like water and isopropanol.

Substituted adamantanes of general formula (30), wherein A², A¹, A⁴, R¹,R², R³, R⁴, D and E are as defined in formula (I), can be prepared asshown in Scheme 8.

Substituted adamantanes of general formula (28) can be dehydrated with areagent like TBTU in the presence of a base like isopropylethylamine ina solvent like N,N-dimethylacetamide to provide nitriles of generalformula (29). Nitriles of general formula (29) can be treated withreagents like trimethyl tin chloride and sodium azide in a solvent liketoluene to provide tetrazoles of general formula (30).

Alternatively, adamantane amines of general formula (31) wherein P ishydrogen or C₁-C₆ alkyl, can be (a) treated with a reagent like CbzCl ina solvent like dichloromethane in the presence of a base likediisopropylethylamine; (b) treating the resulting product with a reagentlike KOTMS in a solvent like THF; and (c) treating the acid from step(b) with ammonia or ammonium hydroxide in the presence of a reagent likeEDCI and HOBt, and a base like diisopropylethylamine, in a solvent likeDMF, to yield adamantane amides of general formula (32) wherein P is aprotecting group like —C(O)OCH₂C₆H₅. The amides of general formula (32)can be (a) treated with a reagent like trifluoroacetic anhydride in asolvent like dichloromethane in the presence of a base liketriethylamine; and (b) treating the intermediate from step (a) with acatalyst like Pd(OH)₂ on carbon under an atmosphere of hydrogen, toprovide amines of formula (33). Amines of general formula (33) can becoupled to acids of general formula (17), in the presence of a reagentlike HATU and a base like diisopropylethylamine, in a solvent like DMF,to provide compounds of general formula (29).

Substituted adamantanes of general formula (34), wherein A², A³, A⁴, R¹,R², R³, R⁴, D and E are as defined in formula I, can be prepared fromtreatment of compounds of formula (29) with hydroxylamine hydrochloridein a solvent like DMSO, in the presence of a base likediisopropylethylamine.

Substituted adamantanes of general formula (37) and (38), wherein A²,A³, A⁴, R¹, R², R³, R⁴, D and E are as defined in formula I, and R¹⁰¹ isalkyl, cycloalkyl, aryl, heteroaryl, or heterocycle, can be prepared asshown in Scheme 10.

Substituted adamantanes of general formula (35) can be (a) treated withtrifluoroacetic anhydride in a solvent like trifluoroacetic acid; and(b) treating the product of step (a) with a thiol of formula R¹⁰¹SH atelevated temperature, typically at about 120° C. for a period of about20 hours, in a solvent like trifluoroacetic acid to provide thioethersof general formula (36). Thioethers of general formula (36) can beoxidized with an oxidizing agent such as, but not limited to,3-chloroperbenzoic acid, in a solvent such as, but not limited to,dichloromethane, to provide sulfoxides of general formula (37) and/orsulfones of general formula (38).

Substituted adamantanes of general formula (42), wherein A², A³, A⁴, R¹,R², R³, R⁴, R²⁵, R²⁶, D and E are as defined in formula (I), can beprepared as shown in Scheme 11.

Substituted adamantanes of general formula (22) wherein P is hydrogen oran acid protecting group such as, but not limited to, C₁-C₆ alkyl, aryl(substituted or unsubstituted) or arylalkyl (substituted orunsubstituted), can be converted alcohols of formula (39) by treatmentwith a reducing agent such as, but not limited to, lithium aluminumhydride or diisobutylaluminum hydride in a solvent like THF. Reaction ofthe alcohols of general formula (39) with trifluoromethanesulfonicanhydride in the presence of a base like pyridine and in a solvent likedichloromethane provides the intermediate triflate that can be isolated.Treatment of the triflate with potassium thioacetate in a solvent likedimethylformamide yields adamantanes of general formula (40). Adamantanethioacetates of general formula (40), when treated with an oxidizingagent such as, but not limited to, hydrogen peroxide and a base likesodium acetate in a solvent like acetic acid provides sulfonic acids ofgeneral formula (41).

Sulfonic acids of general formula (41) can be coupled with an amine offormula R²⁵R²⁶NH wherein R²⁵ and R²⁶ are defined as in formula I toprovide compounds of formula (42). Numerous reaction conditions for sucha conversion are known to one skilled in the art. One such couplingutilizes triphosgene in the presence of a base like triethylamine with acatalytic amount of dimethylformamide in a solvent like dichloromethane,followed by the addition an amine of formula R²⁵R²⁶NH.

Compounds of formula (42) wherein R²⁵ is as defined in formula (I) otherthan hydrogen and R²⁶ is hydrogen, or R²⁵ and R²⁶ are as defined informula (I) other than hydrogen, can also be obtained from the mono ordialkylation of compounds of formula (42) wherein R²⁵ and R²⁶ arehydrogen.

The mono alkylation can be facilitated with an alkylating reagent offormula R²⁵X₁ wherein R²⁵ is methyl, benzyl, and allyl, and X₁ is aleaving group such as, but not limited to, Cl, Br, I, triflate ortosylate. The reaction is generally conducted in the presence of a basesuch as, but not limited to, alkali metal carbonates (for example,cesium carbonate and the like), in a solvent such as, but not limitedto, DMF, providing compounds of formula (42) wherein R²⁵ is methyl,benzyl, and allyl, and R²⁶ is hydrogen. Further alkylation with R²⁶X₁wherein R²⁶ is methyl, benzyl, and allyl and X₁ as defined above, usingthe aforementioned reaction condition, affords compounds of formula (42)wherein R²⁵ and R²⁶ are independently selected from the group consistingof methyl, benzyl, and allyl. The reaction can be conducted stepwise orin situ without isolating the product of the monoalkylation.

Alternatively, compounds of formula (42) wherein R²⁵ and R²⁶ areidentical and are as defined in formula (I) other than hydrogen, can beprepared from the reaction of compounds of formula (42) wherein R²⁵ andR²⁶ are hydrogen and about two equivalents of the alkylating agent.

Substituted adamantanes of general formula (46), wherein A², A³, A⁴, R¹,R², R³, R⁴, R¹⁶, R¹⁷, D and E are as defined in formula (I) can beprepared as shown in Scheme 12.

Substituted adamantanes of general formula (43) can be carbonylated withformic acid and oleum and poured into a solution of formula R¹⁵OH toprovide an adamantane of general formula (44) wherein R^(is) is asdefined in formula (I). Adamantanes of general formula (44) wherein R¹⁵is not hydrogen can be converted to admantanes of formula (44) whereinR¹⁵ is hydrogen using methodologies listed in T. W. Greene, P. G. M.Wuts “Protective Groups in Organic Synthesis” 3^(rd) ed. 1999, Wiley &Sons, Inc. The resulting acids can be coupled to amines of generalformula R¹⁶R¹⁷NH to provide amides of formula (45) in the presence ofcoupling reagents such as, but not limited to, EDCI and HOBt in asolvent like dichloromethane. Adamantanes of general formula (45) may betreated with alcohols or thiols of general formula (15) wherein D is —O—or —S— and E is defined as in formula (I), in the presence of a baselike potassium carbonate in a solvent like toluene to provideadamantanes of general formula (46).

Adamantanes of general formula (46) wherein D is —S— can be converted tocompounds of formula (46) wherein D is —S(O)— or —S(O)₂— by reactingwith an oxidizing agent such as, but not limited to, oxone in a solventlike methanol.

Substituted adamantanes of general formula (54), wherein A², A³, A⁴, R²⁵and R²⁶ are as defined in formula I, may be prepared as shown in Scheme13.

Substituted adamantanes of general formula (47) can be brominated with areagent like hydrobromic acid in a solvent like water to providebromides of general formula (48). Adamantanes of general formula (48)when treated with ethylene glycol and a catalytic amount of an acid likep-toluenesulfonic acid in a solvent like benzene provide adamantanes ofgeneral formula (49). Bromides of general formula (49) can be (a)treated with Rieke zinc in a solvent like tetrahydrofuran; and (b)followed by treatment with reagent (50) (prepared as described in Han,Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am.Chem. Soc. 2002, 124, 7880-7881) in a solvent like tetrahydrofuran toprovide adamantanes of general formula (51). Adamantanes of generalformula (51) may be treated with lithium amide of formula LiNHR²⁵R²⁶(prepared in situ by reacting ammonia with lithium or amines of formulaR²⁵R²⁶NH wherein R²⁵ and R²⁶ are other than hydrogen, with t-butyllithium) in a solvent mixture like ammonia and tetrahydrofuran. Theresulting sulfinamides can be oxidized with a reagent like osmiumtetroxide with a catalyst oxidant like NMO in a solvent liketetrahydrofuran to provide sulfonamides of general formula (52).Adamantanes of general formula (52) can be deketalized with reagentslike hydrochloric acid in a solvent like water and tetrahydrofuran toprovide ketones of formula (53). Ketones of formula (53) can be treatedwith amines of formula R²⁵R²⁶NH followed by reduction with reducingreagents such as, but not limited to, sodium borohydride or hydrogenover Pd/C in a solvent like methanol to provide amines of generalformula (54).

Substituted adamantanes of general formula (55), (56) and (57) whereinR¹⁰² is hydrogen, alkyl or aryl, and A², A³, A⁴, R¹, R², R³, R⁴, R²³,R²⁴, D and E are as defined in formula (I), can be prepared as shown inScheme 14.

Substituted adamantanes of general formula (23) can be treated withreagents like ammonia and glyoxal in a solvent like water to provideimidazoles of general formula (55).

Reaction of compounds of formula (23) with Wittig reagent such as, butnot limited to, triethyl phosphonoacetate and a base like sodium hydridein a solvent like dimethoxyethane provides esters of general formula(56) wherein R¹⁰² is alkyl or aryl. Esters of general formula (56) canbe cleaved with lithium hydroxide in a solvent mixture liketetrahydrofuran and water to provide acids of general formula (56)wherein R¹⁰² is hydrogen.

Adamantanes of general formula (23) can be reductively aminated withamines of general formula R²³R²⁴NH with a reagent like sodiumtriacetoxyborohydride in the presence of an acid like acetic acid in asolvent like dichloroethane to yield amines of general formula (57).

Substituted adamantanes of general formula (60), wherein A², A³, A⁴, R¹,R², R³, R⁴, D and E are as defined in formula I and Q is hydrogen,alkyl, or cycloalkyl, can be prepared as shown in Scheme 15.

Substituted adamantanes of general formula (23) can be treated with areagent like acetylenemagnesium chloride in a solvent like THF to yieldalcohols of general formula (58). Adamantane alcohols of general formula(58) can be oxidized with a reagent like Dess-Martin periodinane in asolvent like dichloromethane to provide alkynones of general formula(59). Alkynones of general formula (59) can be reacted with a reagentlike hydroxylamine hydrochloride in the presence of a base likepotassium carbonate in a solvent like isopropanol to provideheterocycles of general formula (60).

Substituted adamantanes of general formula (61), wherein A², A³, A⁴, R¹,R², R³, R⁴, R²⁰, D and E are as defined in formula (I), can be preparedas shown in Scheme 16.

Adamantanes of general formula (39) can be alkylated with a reagent offormula R²⁰X₁, wherein X₁ is a halide or other leaving group likebromide, iodide, tosylate or triflate, in the presence of a base likesodium hydride in a solvent like dimethylformamide to yield ethers ofgeneral formula (61).

Substituted adamantanes of general formula (63), wherein E is aryl orheteroaryl and A¹, A², A³, A⁴, R¹, R², R³, R⁴, and D are as defined informula (I) and R¹⁰³ and R¹⁰⁴ are alkyl, alkoxyalkyl, cycloalkyl, aryl,heteroaryl, heterocycle, heteroaryl, heteroarylalkyl, cycloalkylalkyl,arylalkyl, heteroarylalkyl, or heterocyclealkyl, or R¹⁰³ and R¹⁰⁴combined to the atom to which they are attached form a heterocycle orheteroaryl can be prepared as shown in Scheme 17.

Substituted adamantanes of general formula (62) wherein X₁ is a halideor triflate can be coupled with amines of formula NHR¹⁰³R¹⁰⁴ with areagent combination like copper iodide and N,N-dimethylglycine in asolvent like DMSO under microwave heating to provide adamantanes ofgeneral formula (63).

Substituted adamantanes of general formula (65), wherein m is 1 or 2,A¹, A², A³, A⁴, R¹, R², R³, R⁴ and D are as defined in formula (I), E isaryl or heteroaryl, and X₂ is halogen, can be prepared as shown inScheme 18.

Adamantanes of general formula (64) can be halogenated with a reagentlike N-bromosuccinimde in the presence of an acid like HBr in a solventlike dichloromethane to yield aryl halides of general formula (65).

It is understood that the schemes described herein are for illustrativepurposes and that routine experimentation, including appropriatemanipulation of the sequence of the synthetic route, protection of anychemical functionality that are not compatible with the reactionconditions and deprotection are included in the scope of the invention.Protection and Deprotection of carboxylic acids and amines are known toone skilled in the art and references can be found in “Protective Groupsin Organic Synthesis”, T. W. Greene, P. G. M. Wuts, 3rd edition, 1999,Wiley & Sons, Inc.

The compounds and processes of the present invention will be betterunderstood by reference to the following Examples, which are intended asan illustration of and not a limitation upon the scope of the invention.Further, all citations herein are incorporated by reference.

Compounds of the invention were named by ACD/ChemSketch version 5.01(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or were given names consistent with ACD nomenclature. Adamantane ringsystem isomers were named according to common conventions. Twosubstituents around a single ring within an adamantane ring system aredesignated as being of Z or E relative configuration (for examples seeC. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem.63: 2758-2760, 1998).

Example 1E-4-(2-methyl-2-phenoxy-propionylamino)-adamantane-1-carboxylic acidamide Example 1A E- and Z-5-hydroxy-2-adamantamine

A solution of 5-hydroxy-2-adamantanone (10 g, 60.161 mmoles) and 4 Åmolecular sieves (5 g) in methanolic ammonia (7N, 100 mL) was stirredovernight at room temperature. The mixture was cooled in an ice bath,treated by the portionwise addition of sodium borohydride (9.1 g, 240.64mmoles) and stirred at room temperature for 2 hours. The mixture wasfiltered and MeOH was removed under reduced pressure. The mixture wastaken into DCM (100 mL), acidified with 1N HCl to pH=3 and the layersseparated. The aqueous layer was treated with 2N NaOH solution to pH=12and extracted three times with 4:1 THF:DCM. The combined organicextracts were dried (MgSO₄) and filtered. The filtrate was concentratedunder reduced pressure to provide the title compound as a white solid(9.84 g, 97.9%).

Example 1B E-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide

A solution of E- and Z-5-hydroxy-2-adamantamine (0.868 g, 5.2 mmoles) inDCM (15.0 mL) and DIPEA (2.5 mL) was cooled in an ice bath and treatedwith 2-bromoisobutyryl bromide (0.72 mL, 5.8 mmoles) in DCM (2.5 mL).The mixture was stirred for 2 hours at room temperature and DCM wasremoved under reduced pressure. The residue was partitioned betweenwater and ethyl acetate. The organic layer was washed with saturatedsodium bicarbonate, water, dried (MgSO₄) and filtered. The filtrate wasconcentrated under reduced pressure to provide the title compound asdark beige solid (1.17 g, 71%). The isomers were separated by columnchromatography (silica gel, 5-35% acetone in hexane) to furnish 0.78 gof E-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide and 0.39g of Z-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide.

Example 1C E-4-(2-bromo-2-methyl-propionylamino)-adamantane-1-carboxylicacid methyl ester

A solution ofE-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide (0.78 g,2.48 mmol) in 99% formic acid (2.5 mL) was added dropwise with vigorousgas evolution over 10 minutes to a rapidly stirred 30% oleum solution(7.5 mL) heated to 60° C. (W. J. le Noble, S. Srivastava, C. K. Cheung,J. Org. Chem. 48: 1099-1101, 1983). Upon completion of addition, more99% formic acid (2.5 mL) was slowly added over the next 10 minutes. Themixture was stirred another 60 minutes at 60° C. and then slowly pouredinto vigorously stirred iced water (30.0 mL) cooled to 0° C. The mixturewas allowed to slowly warm to 23° C., filtered and washed with water toneutral pH (100 mL). The precipitate was dried in a vacuum oven, takeninto MeOH and treated with thionyl chloride at 0° C. (0.2 mL, 2.8mmoles). The reaction mixture was stirred at room temperature for 3hours and then MeOH was evaporated under reduced pressure to provide thetitle compound as an off-white solid.

Example 1DE-4-(2-methyl-2-phenoxy-propionylamino)-adamantane-1-carboxylic acidStep A

A solution of phenol (20.7 mg, 0.22 mmoles) and sodium hydride (60%,10.8 mg, 0.27 mmoles) in toluene (2 mL) was stirred at room temperaturefor 1 hour. ThenE-4-(2-bromo-2-methyl-propionylamino)-adamantane-1-carboxylic acidmethyl ester (71.6 mg, 0.2 mmoles) was added and the resulting mixturewas shaken at 100° C. for 48 hours. After that the reaction mixture wascooled and filtered. The filtrate was concentrated under reducedpressure to provide crude methyl ester of the title compound that waspurified on reverse phase HPLC.

Step B

The methyl ester of the title compound obtained from step A washydrolyzed with 2N aqueous NaOH, THF and ethanol (2:1:1, 2 mL) at roomtemperature overnight. The reaction mixture was acidified with 1N HCland extracted with ethyl acetate. The organic layer was separated,washed with water and brine respectively, dried (MgSO₄) and filtered.The filtrate was concentrated under reduced pressure to provide thetitle compound.

Example 1EE-4-(2-methyl-2-phenoxy-propionylamino)-adamantane-1-carboxylic acidamide

A solution ofE-4-(2-methyl-2-phenoxy-propionylamino)-adamantane-1-carboxylic acid (23mg, 0.064 mmoles) in DCM (2 mL) was treated with HOBt (9.5 mg, 0.07mmoles) and EDCI (14.7 mg, 0.077 mmoles) and stirred at room temperaturefor 1 hour. Excess of aqueous (30%) ammonia (2 mL) was added and thereaction was stirred for additional 20 hours. The layers were separatedand the aqueous layer extracted twice more with methylene chloride (2×2mL). The combined organic extracts were washed with water (3×2 mL),brine (2 mL), dried (MgSO₄) and filtered. The filtrate was concentratedunder reduced pressure to provide the crude title compound that waspurified on reverse phase HPLC to provide the title compound. ¹H NMR(500 MHz, DMSO-D6) δ ppm 7.26-7.31 (m, 2H) 7.25 (d, J=7.49 Hz, 1H) 7.02(t, J=7.33 Hz, 1H) 6.95 (s, 1H) 6.91 (d, J=7.80 Hz, 2H) 6.68 (s, 1H)3.79-3.88 (m, 1H) 1.91 (s, 2H) 1.76-1.87 (m, 5H) 1.71 (s, 2H) 1.65 (d,J=12.79 Hz, 2H) 1.45 (s, 6H) 1.38 (d, J=12.79 Hz, 2H). MS (ESI+) m/z 357(M+H)⁺.

Example 2E-4-[2-methyl-2-(4-(trifluoromethyl-benzyloxy)-propionylamino]-adamantane-1-carboxylicacid amide

The title compound was prepared according to the procedure outlined inExample 1D and 1E substituting 4-(trifluoromethyl)benzyl alcohol forphenol. ¹H NMR (500 MHz, DMSO-D6) δ ppm 7.73 (d, J=8.11 Hz, 2H) 7.62 (d,J=8.11 Hz, 2H) 7.07 (d, J=7.49 Hz, 1H) 6.95 (s, 1H) 6.68 (s, 1H) 4.60(s, 2H) 3.78 (d, J=7.49 Hz, 1H) 1.88 (s, 2H) 1.76-1.85 (m, 5H) 1.72 (s,2H) 1.59 (d, J=13.10 Hz, 2H) 1.39-1.44 (m, 8H). MS (ESI+) m/z 439 (M+H)⁺

Example 3E-4-[2-methyl-2-(2-methyl-cyclohexyloxy)-propionylamino]-adamantane-1-carboxylicacid

A two phase suspension ofE-4-(2-bromo-2-methyl-propionylamino)-adamantane-1-carboxylic acidmethyl ester (71.6 mg, 0.2 mmoles), 2-methylcyclohexanol (0.033 mL, 0.24mmoles) and tetrabutylammonium bromide (6 mg, 0.02 mmoles) in DCM (1.0mL) and 50% aqueous NaOH (1.0 mL) was stirred at room temperature for 20hours. After that the reaction mixture was diluted with DCM, neutralizedwith 3N HCl and layers separated. Organic layer was washed with water(3×2 mL), dried (MgSO₄) and filtered. The filtrate was concentratedunder reduced pressure to provide crude methyl ester of the titlecompound that was purified on reverse phase HPLC and hydrolyzed with 2Naqueous NaOH, THF and ethanol (2:1:1, 2 mL) at room temperature for 20hours. The reaction mixture was acidified with 1N HCl and extracted withethyl acetate. The organic layer was separated, washed with water andbrine respectively, dried (MgSO₄) and filtered. The filtrate wasconcentrated under reduced pressure to provide the title compound. ¹HNMR (400 MHz, DMSO-D6) δ ppm 11.77-12.49 (m, 1H) 7.27 (d, J=7.98 Hz, 1H)3.76 (d, J=6.75 Hz, 1H) 3.19-3.28 (m, 1H) 0.98-1.96 (m, 28H) 0.85-0.96(m, 3H) MS (ESI+) m/z 378 (M+H)⁺

Example 4E-4-[2-methyl-2-(3-methyl-cyclohexyloxy)-propionylamino]-adamantane-1-carboxylicacid

The title compound was prepared according to the procedure outlined inExample 3 substituting 3-methylcyclohexanol for 2-methylcyclohexanol. ¹HNMR (400 MHz, DMSO-D6) δ ppm 11.70-12.38 (m, 1H) 7.16 (d, J=7.36 Hz, 1H)3.76 (s, 1H) 3.41-3.53 (m, 1H) 1.33-1.96 (m, 18H) 1.05-1.31 (m, 8H)0.66-0.99 (m, 5H). MS (ESI+) m/z 378 (M+H)⁺

Example 5E-4-(2-cycloheptyloxy-2-methyl-propionylamino)-adamantane-1-carboxylicacid

The title compound was prepared according to the procedure outlined inExample 3 substituting cycloheptanol for 2-methylcyclohexanol. ¹H NMR(400 MHz, DMSO-D6) δ ppm 11.85-12.35 (m, 1H) 7.21 (d, J=7.67 Hz, 1H)3.70-3.88 (m, 2H) 1.37-1.96 (m, 25H) 1.27 (s, 6H). MS (ESI+) m/z 378(M+H)⁺

Example 6E-4-(2-(cyclohexylmethoxy-2-methyl-propionylamino)-adamantane-1-carboxylicacid

The title compound was prepared according to the procedure outlined inExample 3 substituting cyclohexylmethanol for 2-methylcyclohexanol. ¹HNMR (400 MHz, DMSO-D6) δ ppm 11.70-12.50 (m, 1H) 7.06 (d, J=7.36 Hz, 1H)3.76 (d, J=7.98 Hz, 1H) 3.19 (d, J=6.14 Hz, 2H) 1.41-1.95 (m, 19H) 1.26(s, 6H) 0.90-1.25 (m, 5H). MS (ESI+) m/z 378 (M+H)⁺

Example 7E-4-[2-(4-chloro-phenoxy)-2-methyl-proprionylamino]-adamantane-1-carboxylicacid Example 7A E-4-Amino-adamantane-1-carboxylic acid

To 1.0 g (10 wt %) of 5% Pd/C is added 4-oxo-adamantane-1-carboxylicacid (10.0 g, 51.5 mmol) followed by 7M NH₃ in MeOH (200 mL). Thereaction mixture is stirred under an atmosphere of H₂ at 23° C. for16-24 hours; water (200 mL) is added; and the catalyst is removed byfiltration. The catalyst is washed with methanol and the filtratesolution is concentrated under reduced pressure at a bath temperature of35° C. until solvent stops coming over. Approximately 150 mL of a slurryremains. Acetonitrile (300 mL) is added to the slurry which is thenstirred for 3 hours at 23° C. The slurry is filtered and washed oncewith acetonitrile (100 mL). The wet cake is dried at 50° C. and 20 mmHgunder N₂ to yield E-4-amino-adamantane-1-carboxylic acid (8.65 g, 86%,13.1:1.0 E:Z ratio by ¹H-NMR in D₂O).

Example 7B E-4-Amino-adamantane-1-carboxylic acid methyl ester

Methanol (85 mL) was cooled to 0° C.; acetyl chloride (15.5 mL) wasadded dropwise; and then the solution was warmed to 23° C. for 15-20minutes. E-4-Amino-adamantane-1-carboxylic acid (8.53 g, 43.7 mmol) wasadded and the reaction solution was heated to 45° C. for 16 hours. Thereaction solution was cooled to 23° C. and acetonitrile (85 mL) wasadded. The reaction solution was concentrated under reduced pressure to˜¼ volume. The reaction solution was further chase distilled withacetonitrile (2×85 mL). The resulting suspension was cooled to 23° C.and filtered. The filtrate was recirculated twice to wash the wet cake.The product was dried at 50° C., 20 mmHg for 16 hours to affordE-4-amino-adamantane-1-carboxylic acid methyl ester as a whitecrystalline solid (10.02 g, 93%).

Example 7CE-4-[2-(4-chloro-phenoxy)-2-methyl-propionylamino]-adamantane-1-carboxylicacid

To the solution of E-4-Adamantamine-1-carboxylic acid methyl ester (49mg, 0.2 mmoles) and triethylamine (0.097 mL, 0.7 mmoles) in DCM (1.0 mL)was added a solution of 2-(4-chlorophenoxy)-2-methylpropionyl chloride(55 mg, 0.24 mmoles) in DCM (1.0 mL). The resulting reaction mixture wasstirred at room temperature for 20 hours and concentrated under reducedpressure. The residue was partitioned between ethylacetate and water.The organic layer was separated and washed with 1N HCl, water and brine,dried (MgSO4) and filtered. The filtrate was concentrated under reducedpressure to provide the crude methyl ester of the title compound thatwas purified on reverse phase HPLC and hydrolyzed with 2N aqueous NaOH,THF and ethanol (2:1:1, 2 mL) at room temperature for 20 hours. Thereaction mixture was acidified with 1N HCl and extracted with ethylacetate. The organic layer was separated, washed with water and brinerespectively, dried (MgSO₄) and filtered. The filtrate was concentratedunder reduced pressure to provide the title compound. ¹H NMR (500 MHz,DMSO-D6) δ ppm 11.94-12.25 (m, 1H) 7.30-7.36 (m, 3H) 6.87-6.94 (m, 2H)3.80-3.87 (m, 1H) 1.93 (s, 2H) 1.85 (d, J=2.44 Hz, 3H) 1.80 (d, J=2.75Hz, 2H) 1.75 (s, 2H) 1.68 (d, J=12.82 Hz, 2H) 1.46 (s, 6H) 1.38 (d,J=12.82 Hz, 2H). MS (ESI+) m/z 392 (M+H)⁺

Example 8E-4-[2-(4-chloro-phenoxy)-2-methyl-propionylamino]-adamantane-1-carboxylicacid amide

The title compound was prepared according to the procedure outlined inExample 1E fromE-4-[2-(4-chloro-phenoxy)-2-methyl-propionylamino]-adamantane-1-carboxylicacid (Example 7C). ¹H NMR (400 MHz, DMSO-D6) δ ppm 7.25-7.36 (m, 3H)6.94-6.99 (m, 1H) 6.89-6.94 (m, 2H) 6.69 (s, 1H) 3.83 (d, J=7.67 Hz, 1H)1.91 (s, 2H) 1.75-1.87 (m, 5H) 1.63-1.73 (m, 4H) 1.46 (s, 6H) 1.32-1.42(m, 2H). MS (ESI+) m/z 391 (M+H)⁺

Example 9E-4-[2-methyl-2-(4-methyl-cyclohexyloxy)-propionylamino]-adamantane-1-carboxylicacid amide

The title compound was prepared according to the procedures outlined inExample 3 and 1E, substituting 4-methylcyclohexanol for2-methylcyclohexanol. ¹H NMR (400 MHz, DMSO-D6) δ ppm 7.14 (d, 1H) 6.98(s, 1H) 6.70 (s, 1H) 3.72-3.82 (m, 1H) 3.39-3.50 (m, 1H) 1.19-1.96 (m,26H) 0.91-1.05 (m, 2H) 0.81-0.89 (m, 3H). MS (ESI+) m/z 377 (M+H)⁺.

Example 10 E-4-[(2-phenoxypropanoyl)amino]adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 7C and 1E substituting 2-phenoxy-propionyl chloride for2-(4-chlorophenoxy)-2-methylpropionyl chloride. ¹H NMR (400 MHz,DMSO-D6) δ ppm 7.74 (d, J=7.36 Hz, 1H) 7.26 (t, J=7.98 Hz, 2H) 6.83-6.99(m, 4H) 6.68 (s, 1H) 4.86 (q, J=—6.55 Hz, 1H) 3.78 (d, J=7.06 Hz, 1H)1.69-1.92 (m, 11H) 1.43 (d, J=6.44 Hz, 3H) 1.37 (d, J=12.89 Hz, 2H). MS(ESI+) m/z 343 (M+H)⁺

Example 11E-4-{[2-methyl-2-(2-methylphenoxy)propanoyl]amino}adamantane-1-carboxylicacid

The title compound was prepared according to the procedure outlined inExample 1D substituting 2-methylphenol for phenol. ¹H NMR (500 MHz,DMSO-D6) δ ppm 11.58-12.61 (br. s, 1H) 7.28 (d, J=7.32 Hz, 1H) 7.19 (d,J=7.32 Hz, 1H) 7.05-7.13 (m, 1H) 6.91 (t, J=6.87 Hz, 1H) 6.82 (d, J=7.93Hz, 1H) 3.79-3.88 (m, 1H) 2.22 (s, 3H) 1.95 (s, 2H) 1.86 (d, J=2.75 Hz,3H) 1.82 (s, 2H) 1.76 (s, 2H) 1.68 (d, J=13.12 Hz, 2H) 1.46 (s, 6H) 1.43(d, J=13.73 Hz, 2H). MS (ESI+) m/z 372 (M+H)⁺

Example 12E-4-{[2-methyl-2-(4-methylphenoxy)propanoyl]amino}adamantane-1-carboxylicacid

The title compound was prepared according to the procedure outlined inExample 1D substituting 4-methylphenol for phenol. ¹H NMR (500 MHz,DMSO-D6) δ ppm 11.75-12.46 (br.s, 1H) 7.30 (d, J=7.32 Hz, 1H) 7.08 (d,J=8.24 Hz, 2H) 6.81 (d, J=8.54 Hz, 2H) 3.80-3.86 (m, 1H) 2.23 (s, 3H)1.94 (s, 2H) 1.86 (d, J=2.44 Hz, 3H) 1.82 (s, 2H) 1.76 (s, 2H) 1.69 (d,J=12.82 Hz, 2H) 1.38-1.45 (m, 8H). MS (ESI+) m/z 372 (M+H)⁺

Example 13E-4-{[2-(2-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid

The title compound was prepared according to the procedure outlined inExample 1D substituting 2-chlorophenol for phenol. ¹H NMR (500 MHz,DMSO-D6) 5 ppm 11.50-12.76 (br. s, 1H) 7.63 (d, J=7.63 Hz, 1H) 7.57 (dd,J=7.93, 1.53 Hz, 1H) 7.36 (t, 1H) 7.24 (dd, J=8.24, 1.22 Hz, 1H) 7.16(t, 1H) 3.88-3.98 (m, 1H) 2.04 (s, 2H) 1.94 (d, J=2.44 Hz, 5H) 1.82-1.88(m, 4H) 1.52-1.59 (m, 8H). MS (ESI+) m/z 392 (M+H)⁺

Example 14E-4-{[2-(2-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 1D and 1E substituting 2-methoxyphenol for phenol. ¹H NMR (400MHz, DMSO-D6) δ ppm 7.91 (d, J=7.67 Hz, 1H) 7.05-7.11 (m, 3H) 7.00 (s,1H) 6.86-6.93 (m, 1H) 6.71 (s, 1H) 3.81-3.88 (m, 1H) 3.79 (s, 3H) 1.96(s, 2H) 1.76-1.92 (m, 9H) 1.54 (d, J=13.20 Hz, 2H) 1.36 (s, 6H). MS(ESI+) m/z 387 (M+H)⁺

Example 15E-4-{[2-(4-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 1D and 1E substituting 4-methoxyphenol for phenol. ¹H NMR (400MHz, DMSO-D6) δ ppm 7.30 (d, J=7.36 Hz, 1H) 6.93-7.01 (m, 1H) 6.82-6.92(m, 4H) 6.70 (s, 1H) 3.85 (d, J=7.06 Hz, 1H) 3.71 (s, 3H) 1.92-1.97 (m,2H) 1.77-1.89 (m, 5H) 1.74 (s, 3H) 1.71 (s, 1H) 1.44 (d, J=12.58 Hz, 2H)1.37 (s, 6H). MS (ESI+) m/z 387 (M+H)⁺

Example 16E-4-({2-methyl-2-[3-(trifluoromethyl)phenoxyl]propanoyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 1D and 1E substituting 3-trifluoromethylphenol for phenol. ¹HNMR (400 MHz, DMSO-D6) δ ppm 7.53 (t, J=7.98 Hz, 1H) 7.37 (dd, J=12.12,7.21 Hz, 2H) 7.19 (dd, 1H) 7.14 (s, 1H) 6.95 (s, 1H) 6.68 (s, 1H) 3.81(s, 1H) 1.90 (s, 2H) 1.80 (d, J=7.67 Hz, 4H) 1.76 (s, 1H) 1.70 (s, 2H)1.61 (d, 2H) 1.52 (s, 6H) 1.32 (d, J=13.50 Hz, 2H). MS (ESI+) m/z 425(M+H)⁺

Example 17E-4-{[2-(3-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 1D and 1E substituting 3-methoxyphenol for phenol. ¹H NMR (500MHz, DMSO-D6) δ ppm 7.26 (d, J=7.32 Hz, 1H) 7.17 (t, J=8.24 Hz, 1H) 6.98(s, 1H) 6.71 (s, 1H) 6.60 (dd, J=8.39, 1.98 Hz, 1H) 6.43-6.48 (m, 2H)3.82 (d, J=7.02 Hz, 1H) 3.70 (s, 3H) 1.91 (s, 2H) 1.76-1.86 (m, 5H) 1.71(s, 2H) 1.66 (d, J=12.82 Hz, 2H) 1.46 (s, 6H) 1.36 (d, J=12.51 Hz, 2H).MS (ESI+) m/z 387 (M+H)⁺

Example 18 N-adamantan-2-yl-2-(4-chloro-phenoxy)-2-methyl-propionamide

The title compound was prepared according to the procedure outlined inExample 7C substituting 4-adamantamine hydrochloride forE-4-adamantamine-1-carboxylic acid methyl ester. ¹H NMR (400 MHz,DMSO-D6) δ ppm 7.30-7.35 (m, 2H) 7.25 (d, J=7.36 Hz, 1H) 6.89-6.94 (m,2H) 3.83-3.91 (m, 1H) 1.82 (d, J=10.74 Hz, 2H) 1.77 (s, 5H) 1.64-1.73(m, 5H) 1.42-1.49 (m, 8H). MS (ESI+) m/z 348 (M+H)⁺.

Example 19E-2-(4-Chloro-phenoxy)-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide

The title compound was prepared according to the procedure outlined inExample 7C substituting E-4-aminoadamantan-1-ol forE-4-adamantamine-1-carboxylic acid methyl ester. ¹H NMR (400 MHz,DMSO-D6) δ ppm 7.30-7.35 (m, 2H) 7.22 (d, J=7.06 Hz, 1H) 6.88-6.94 (m,2H) 4.21-4.52 (br s, 1H) 3.75-3.80 (m, 1H) 1.96 (s, 2H) 1.91 (s, 1H)1.64-1.71 (m, 2H) 1.53-1.62 (m, 6H) 1.45 (s, 6H) 1.27 (d, J=12.58 Hz,2H). MS (ESI+) m/z 364 (M+H)⁺.

Example 20E-{[2-Methyl-2-(4-methylphenoxy)propanoyl]amino}adamantane-1-carboxamide

A solution of the product of Example 12 (24 mg, 0.064 mmol) in DCM (2mL) was treated with HOBt (9.5 mg, 0.07 mmol) and EDCI (14.7 mg, 0.077mmol) and stirred at room temperature for 1 hour. Excess of aqueous(30%) ammonia (2 mL) was added and the reaction was stirred foradditional 20 hours. The layers were separated and the aqueous layerextracted with DCM (2×2 mL). The combined organic extracts were washedwith water (3×2 mL), brine (2 mL), dried (MgSO₄) and filtered. Thefiltrate was concentrated under reduced pressure to provide the crudecompound that was purified by reverse phase preparative HPLC on a WatersSymmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradientof 10% to 100% acetonitrile:0.1% aqueous TFA over 8 min (10 min runtime) at a flow rate of 40 mL/min. to provide the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 7.28 (d, J=7.36 Hz, 1H), 7.08 (d, J=8.12 Hz,2H), 6.98-6.99 (bs, 1H), 6.80-6.82 (m, 2H), 6.71-6.73 (bs, 1H),3.81-3.86 (m, 1H), 2.23 (s, 3H), 1.91-1.93 (m, 2H), 1.77-1.87 (m, 5H),1.71-1.73 (m, 2H), 1.65-1.70 (m, 2H), 1.41 (s, 6H), 1.37-1.42 (m, 2H).MS (ESI+) m/z 371 (M+H)⁺.

Example 21E-4-{[2-(3-Chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamideExample 21A

Example 21A was prepared according to the procedure outlined in Example1D, substituting 3-chlorophenol for phenol.

Example 21BE-4-{[2-(3-Chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, substituting the product of Example 21A for the product ofExample 1D. ¹H NMR (500 MHz, DMSO-d) δ ppm 7.35 (d, J=6.93 Hz, 1H), 7.31(t, J=8.10 Hz, 1H), 7.07 (dd, J=7.83, 1.91 Hz, 1H), 6.97-6.98 (bs, 1H),6.92 (t, J=2.15 Hz, 1H), 6.87 (dd, J=8.22, 2.29 Hz, 1H), 6.70-6.72 (bs,1H), 1.90-1.93 (m, 2H), 1.70-1.71 (m, 2H), 1.49 (s, 6H), 3.80-3.84 (m,1H), 1.76-1.85 (m, 5H), 1.60-1.68 (m, 2H), 1.33-1.37 (m, 2H). MS (ESI+)m/z 391 (M+H)⁺.

Example 22E-4-({2-Methyl-2-[4-(trifluoromethoxy)phenoxy]propanoyl}amino)adamantane-1-carboxamideExample 22A

Example 22A was prepared according to the procedure outlined in Example1D, substituting 4-trifluoromethoxyphenol for phenol.

Example 22BE-4-({2-Methyl-2-[4-(trifluoromethoxy)phenoxy]propanoyl}amino)adamantane-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, substituting the product of Example 22A for the product ofExample 1D. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.41 (t, J=8.25 Hz, 1H),7.33 (d, J=6.94 Hz, 1H), 7.00 (d, J=8.15 Hz, 1H), 6.90-6.96 (m, 2H),6.82-6.84 (bs, 1H), 6.67-6.69 (bs, 1H), 3.79-3.84 (m, 1H), 1.87-1.90 (m,2H), 1.75-1.86 (m, 5H), 1.69-1.71 (m, 2H), 1.63-1.69 (m, 2H), 1.51 (s,6H), 1.29-1.37 (m, 2H). MS (ESI+) m/z 441 (M+H)⁺.

Example 23E-4-{[2-(3-Bromophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid

The title compound was prepared according to the procedure outlined inExample 1D, substituting 3-bromo-phenol for phenol. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.05-12.10 (s, 1H), 7.38 (d, J=6.82 Hz, 1H), 7.19-7.27(m, 2H), 7.06 (t, J=2.06 Hz, 1H), 6.91 (ddd, J=8.09, 2.36, 1.18 Hz, 1H),3.80-3.84 (m, 1H), 1.93-1.96 (m, 2H), 1.84-1.85 (m, 4H), 1.77-1.80 (m,1H), 1.74-1.76 (m, 2H), 1.65-1.70 (m, 2H), 1.48 (s, 6H), 1.36-1.40 (m,2H). MS (ESI+) m/z 437 (M+H)⁺.

Example 244-{[((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)carbonyl]amino}methyl)benzoicacid

To a solution of the product of Example 7C (200 mg, 0.51 mmol) and TBTU(246 mg, 0.77 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine(0.27 mL, 1.53 mmol) followed by 4-aminomethyl-benzoic acid methyl esterhydrochloride (123 mg, 0.61 mmol) and stirred at room temperature for 20hours. The reaction mixture was concentrated in vacuo. The residue wastaken in ethyl acetate and washed with water and brine respectively,dried (MgSO₄) and concentrated in vacuo to get crude methyl ester of thetitle compound that was purified by reverse phase preparative HPLC on aWaters Symmetry C8 column (40 mm×100 mm, 7 um particle size) using agradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 12 min (15min run time) at a flow rate of 70 mL/min. and concentrated. The methylester of the title compound was hydrolyzed as described in step B ofExample 1D. The crude acid product was purified by reverse phasepreparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 umparticle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueousTFA over 12 min (15 min run time) at a flow rate of 70 mL/min. toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.77-12.82(bs, 1H), 8.08 (t, J=5.96 Hz, 1H), 7.88 (d, J=7.99 Hz, 2H), 7.29-7.36(m, 5H), 6.91-6.93 (m, 2H), 4.31 (d, J=5.86 Hz, 2H), 3.84-3.89 (m, 1H),1.93-1.96 (m, 2H), 1.82-1.91 (m, 5H), 1.77-1.79 (m, 2H), 1.67-1.72 (m,2H), 1.47 (s, 6H), 1.32-1.45 (m, 2H). MS (ESI+) m/z 525 (M+H)⁺.

Example 25E-4-{[2-(2,3-Dimethylphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid Example 25A 2-(2,3-Dimethylphenoxy)-2-methyl-propionic acid

To an ice cold solution of 2,3-dimethylphenol (136 mg, 1.0 mmol) and1,1,1-trichloro-2-methyl-2-propanol hydrate (492 mg, 2.75 mmol) inacetone (2 mL) was added powdered sodium hydroxide (393 mg, 9.83 mmol)in three equal portions at 1 hour interval. After each addition reactionmixture was allowed to come to room temperature. Before last addition ofsodium hydroxide, acetone (2 mL) was added to the reaction mixture. Thereaction mixture was stirred at room temperature for 48 hours andconcentrated in vacuo. The residue was diluted with water and acidifiedto pH 1 with aqueous HCl and extracted with diethyl ether (3×5 mL). Theorganic layers were pooled, dried (Na₂SO₄) and filtered. The filtratewas concentrated under reduced pressure to provide the crude that waspurified by reverse phase preparative HPLC on a Waters Symmetry C8column (40 mm×100 mm, 7 um particle size) using a gradient of 10% to100% acetonitrile:0.1% aqueous TFA over 12 min (15 min run time) at aflow rate of 70 mL/min. to provide the title compound as a pale yellowsolid (158 mg, 76%).

Example 25BE-4-{[2-(2,3-Dimethylphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid

To a solution of the product of Example 25A (20.8 mg, 0.1 mmol) and TBTU(48 mg, 0.15 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine(0.052 mL, 0.3 mmol) followed by the product of Example 7B (30 mg, 0.12mmol) and stirred at room temperature for 20 hours. The reaction mixturewas concentrated in vacuo. The residue was purified by reverse phasepreparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 umparticle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueousTFA over 8 min (10 min run time) at a flow rate of 40 mL/min. andhydrolyzed as described in step B of Example 1D to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.03-12.14 (bs, 1H), 7.30 (d,J=7.30 Hz, 1H), 6.98 (t, J=7.79 Hz, 1H), 6.84 (d, J=7.44 Hz, 1H), 6.68(d, J=8.14 Hz, 1H), 3.84-3.88 (m, 1H), 2.22 (s, 3H), 2.14 (s, 3H),1.95-1.97 (m, 2H), 1.83-1.88 (m, 5H), 1.76-1.78 (m, 2H), 1.69-1.73 (m,2H), 1.41-1.48 (m, 2H), 1.43 (s, 6H). MS (ESI+) m/z 386 (M+H)⁺.

Example 26 tert-Butyl4-(2-{[(E)-5-(aminocarbonyl)-2-adamantyl]amino}-1,1-dimethyl-2-oxoethoxy)phenylcarbamateExample 26A

Example 26A was prepared according to the procedure outlined in Example25A, substituting (4-hydroxy-phenyl)-carbamic acid tert-butyl ester for2,3-dimethylphenol.

Example 26B

Example 26B was prepared using the procedure as described in Example25B, substituting the product of Example 26A for the product of Example25A.

Example 26C tert-Butyl4-(2-{[(E)-5-(aminocarbonyl)-2-adamantyl]amino}-1,1-dimethyl-2-oxoethoxy)phenylcarbamate

The title compound was prepared using the procedure as described inExample 1E, substituting the product of Example 26B for the product ofExample 1D. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.18-9.20 (bs, 1H), 7.34 (d,J=8.50 Hz, 2H), 7.28 (d, J=7.37 Hz, 1H), 6.96-6.98 (bs, 1H), 6.84 (d,J=8.77 Hz, 2H), 6.68-6.70 (bs, 1H), 3.81-3.87 (m, 1H), 1.92-1.95 (m,2H), 1.80-1.89 (m, 5H), 1.68-1.75 (m, 4H), 1.46 (s, 9H), 1.39-1.46 (m,2H), 1.39 (s, 6H). MS (ESI+) m/z 472 (M+H)⁺.

Example 27E-N-[4-(Aminocarbonyl)benzyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 1E substituting the product of Example 24 for the product ofExample 1D. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.03-8.08 (m, 1H), 7.86-7.88(bs, 1H), 7.80 (d, J=8.09 Hz, 2H), 7.32-7.35 (m, 2H), 7.26-7.32 (m, 2H),7.24-7.27 (m, 2H), 6.91-6.93 (m, 2H), 4.29 (d, J=5.87 Hz, 2H), 3.83-3.89(m, 1H), 1.82-1.96 (m, 7H), 1.77-1.79 (m, 2H), 1.66-1.72 (m, 2H), 1.46(s, 6H), 1.37-1.42 (m, 2H). MS (ESI+) m/z 524 (M+H)⁺.

Example 28E-N-[4-(Aminocarbonyl)methyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamideExample 28A

Example 28A was prepared according to the procedure outlined in Example24, substituting glycine methyl ester hydrochloride for4-aminomethyl-benzoic acid methyl ester hydrochloride.

Example 28BE-N-[4-(Aminocarbonyl)methyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, substituting the product of Example 28A for the product ofExample 1D. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.49-7.54 (m, 1H), 7.32-7.35(m, 2H), 7.31 (d, J=7.21 Hz, 1H), 7.08-7.11 (bs, 1H), 6.93-6.97 (m, 1H),6.91-6.93 (m, 2H), 3.82-3.87 (m, 1H), 3.58 (d, J=5.68 Hz, 2H), 1.92-1.98(m, 2H), 1.80-1.90 (m, 5H), 1.74-1.76 (m, 2H), 1.65-1.71 (m, 2H), 1.46(s, 6H), 1.36-1.41 (m, 2H). MS (ESI+) m/z 448 (M+H)⁺.

Example 293-({[((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)carbonyl]amino}methyl)benzoicacid

The title compound was prepared according to the procedure outlined inExample 24, substituting 3-aminomethyl-benzoic acid methyl esterhydrochloride for 4-aminomethyl-benzoic acid methyl ester hydrochloride.¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.81-12.91 (m, 1H), 8.06-8.12 (m, 1H),7.77-7.82 (m, 2H), 7.40-7.44 (m, 2H), 7.31-7.35 (m, 2H), 7.30-7.32 (m,1H), 6.91-6.93 (m, 2H), 4.30 (d, J=5.89 Hz, 2H), 3.83-3.88 (m, 1H),1.93-1.96 (m, 2H), 1.82-1.90 (m, 5H), 1.77-1.79 (m, 2H), 1.67-1.72 (m,2H), 1.46 (s, 6H), 1.37-1.42 (m, 2H). MS (ESI+) m/z 525 (M+H)⁺.

Example 30E-4-({2-[(5-Bromopyridin-2-yl)oxy]-2-methylpropanoyl}amino)adamantane-1-carboxamideExample 30A 2-(5-Bromo-pyridin-2-yloxy)-2-methyl-propionic acid Step A

To a stirred and cooled (0° C.) solution of 2-hydroxy-2-methyl-propionicacid methyl ester (2.6 mL, 22.70 mmol) and 5-bromo-2-fluoro-pyridine(3.32 g, 18.92 mmol) in THF (26 mL) and DMPU (13 mL) was addedportionwise NaH (1 g, 60% in oil, 24.59 mmol). After the addition, theresulting mixture was warmed to room temperature and stirred overnight.Saturated NH₄Cl was then added to quench the reaction and Et₂O was usedto partition the mixture. The organic phase was washed with water,brine, dried over MgSO₄, and filtered. After concentration, the residuewas purified over silica gel using 20% EtOAc/hexane and concentrated togive a clear oil.

Step B

The product of Step A (1.56 g, 5.71 mmol) was dissolved in THF (30 mL)and KOTMS (1.1 g, 8.57 mmol) was added in one portion. The resultingsolution was stirred at room temperature overnight. Et₂O (30 mL) andwater (40 mL) were added to the reaction to partition the mixture. Thephases were separated, and the aqueous phase was acidified using 10%NaHSO₄ solution and extracted with EtOAc. The combined organic phaseswere dried over MgSO₄, filtered and concentrated to give the titlecompound as a white solid.

Example 30BE-4-({2-[(5-Bromopyridin-2-yl)oxy]-2-methylpropanoyl}amino)adamantane-1-carboxamideStep A

HATU (2.46 g, 6.48 mmol) was added in one portion to a solution of theproduct of Step B of Example 30A (1.40 g, 5.40 mmol), the product ofExample 7B (1.45 g, 5.95 mmol), and DIPEA (2.82 mL, 16.2 mmol) in dryCH₂Cl₂ (20 mL). The resulting solution was allowed to stir at roomtemperature overnight before it was diluted with CH₂Cl₂ and washed withaqueous NaHSO₄ solution, 1 M NaOH, dried (Na₂SO₄) and evaporated. Theresidue was purified over silica gel using 30% EtOAc/hexanes andconcentrated to give an oil.

Step B

To the product of Step A (2.27 g, 5.04 mmol) in THF (15 mL) was addedKOTMS (1.42 g, 11.08 mmol) and the resulting solution was stirred atroom temperature overnight before it was diluted with Et₂O and water.The phases were separated and the aqueous phase was acidified withNaHSO₄ solution and extracted with EtOAc. The combined organic phaseswere dried (MgSO₄) and evaporated to give a white solid.

Step C

EDCI (1.40 g, 7.25 mmol) was added to a solution of the product of StepB (2.17 g, 4.84 mmol), HOBt (1.17 g, 8.71 mmol), DIPEA (2.5 mL, 14.4mmol) in dry CH₂Cl₂ (20 mL). The resulting solution was allowed to stirat room temperature for 1 hr before NH₃ solution was added (12 mL, 2M iniPrOH). The mixture was stirred for 2 hours at 25° C., diluted withCH₂Cl₂ and washed with NaHSO₄ solution, 1M NaOH, brine, dried (Na₂SO₄)and evaporated. The residue was purified over silica gel using 5%MeOH/CH₂Cl₂ to give the title compound as a white solid. ¹H NMR (300MHz, CD₃OD) δ ppm 8.11 (d, J=2.52 Hz, 1H), 7.82 (dd, J=8.74, 2.60 Hz,1H), 6.84 (d, J=8.74 Hz, 1H), 3.89-3.92 (m, 1H), 1.91-1.99 (m, 6H), 1.83(s, 3H), 1.66 (s, 6H), 1.41-1.62 (m, 4H). MS (ESI+) m/z 436 (M+H).

Example 31E-4-{[2-(2-Cyanophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamideExample 31A

Example 31A was prepared according to the procedure outlined in Example25A, substituting 2-hydroxy-benzonitrile for 2,3-dimethylphenol.

Example 31B

Example 31B was prepared using the procedure as described in Example25B, substituting the product of Example 31A for the product of Example25A.

Example 31CE-4-{[2-(2-Cyanophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, substituting the product of Example 31B for the product ofExample 1D. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.78 (dd, J=7.68, 1.75 Hz,1H), 7.62 (ddd, J=8.54, 7.48, 1.68 Hz, 1H), 7.49 (d, J=6.94 Hz, 1H),7.17 (td, J=7.58, 0.87 Hz, 1H), 7.08 (d, J=8.53 Hz, 1H), 6.98-6.99 (bs,1H), 6.71-6.72 (bs, 1H), 3.83-3.87 (m, 1H), 1.94-1.96 (m, 2H), 1.75-1.88(m, 7H), 1.71-1.73 (m, 2H), 1.60 (s, 6H), 1.35-1.39 (m, 2H). MS (ESI+)m/z 382 (M+H).

Example 32E-4-{[2-(4-Hydroxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamideExample 32A

Example 32A was prepared according to the procedure outlined in Example25A, substituting 4-benzyloxy-phenol for 2,3-dimethylphenol.

Example 32B

Example 32B was prepared according to the procedure outlined in Example25B, substituting the product of Example 32A for the product of Example25A.

Example 32C

Example 32C was prepared according to the procedure outlined in Example1E, substituting the product of Example 32B for the product of Example1D.

Example 32DE-4-{[2-(4-Hydroxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The product of Example 32C (62 mg, 0.13 mmol) was debenzylated using 20%Pd(OH)₂/C (63 mg) and methanol (2 mL) at 60 psi at room temperature for20 hours. The reaction mixture was filtered and concentrated underreduced pressure to provide the crude product that was purified byreverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40mL/min. to provide title compound as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.12 (s, 1H), 7.28 (d, J=7.49 Hz, 1H), 6.96-6.99 (bs,1H), 6.77-6.79 (m, 2H), 6.69-6.71 (bs, 1H), 6.63-6.69 (m, 2H), 3.81-3.87(m, 1H), 1.93-1.95 (m, 2H), 1.78-1.89 (m, 5H), 1.69-1.76 (m, 4H),1.42-1.47 (m, 2H), 1.35 (s, 6H). MS (ESI+) m/z 373 (M+H)⁺.

Example 33((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)aceticacid Example 33A2-(4-chlorophenoxy)-N-[(E)-5-(hydroxymethyl)-2-adamantyl]-2-methylpropanamide

To a cold (−30° C.) solution of the methyl ester of Example 7C (870 mg,2.15 mmol) in THF (3.0 mL) was added 1N LAH in THF solution (3.22 ml,3.22 mmol) slowly under N₂ flow. The reaction mixture was stirred from−30° C. to 0° C. for 3 hours. It was quenched with water carefully,acidified with 1N HCl and extracted with DCM 3 times. The combinedorganic layer was dried over Na₂SO₄, filtered, concentrated underreduced pressure and the residue purified by flash chromatography with30% ethyl acetate/70% hexane to provide the title compound (690 mg,85%). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.32-9.39 (m, 1H), 7.17-7.29 (m,2H), 7.00 (d, 1H), 6.81-6.91 (m, 2H), 3.99-4.12 (m, 1H), 1.44-2.15 (m,21H). MS (ESI+) m/z 378 (M+H)⁺.

Example 33BE-4-[2-(4-Chlorophenoxy)-2-methyl-propionylamino]-adamantane-1-carbaldehyde

To a solution of the product of Example 33A (990 mg, 2.63 mmol) in DCE(8.0 mL) were added NMO (461 mg, 3.94 mmol), TPAP (46 mg, 0.13 mmol) andmolecular sieves at room temperature under N₂ flow. The reaction mixturewas stirred overnight at room temperature. It was filtered throughCelite and washed with DCM 3 times. The combined filtrate wasconcentrated under reduced pressure and purified by flash chromatographywith 30% ethyl acetate/70% hexane to provide the title compound (740 mg,75%). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.36 (m, 1H), 7.20-7.26 (m, 2H),6.95-7.05 (m, 1H), 6.82-6.91 (m, 2H), 4.00-4.10 (m, 1H), 1.48-2.13 (m,19H). MS (ESI+) m/z 376 (M+H)⁺.

Example 33CE-{4-[2-(4-Chlorophenoxy)-2-methyl-propionylamino]-adamantan-1-yl}-acetonitrile

To a cold (0° C.) solution of the product of Example 33B (375 mg, 1mmol) in DME (5.0 mL)/EtOH (0.15 ml) was added TosMIC (254 mg, 1.3 mmol)and t-BuOK (281 mg, 2.5 mmol) under N₂ flow. The reaction mixture wasstirred at room temperature for 2 hrs, then heated to 35-40° C. for 30minutes. It was filtered through Al₂O₃ plug after it was cool down toroom temperature and washed with DME (3×). The combined filtrate wasconcentrated under reduced pressure and purified by flash chromatographywith 30% ethyl acetate/70% hexane to provide the title compound (200 mg,52%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.19-7.29 (m, 2H), 6.91-7.01 (m,1H), 6.81-6.90 (m, 2H), 3.96-4.05 (m, 1H), 2.14 (s, 2H), 1.94-2.08 (m,3H), 1.47-1.75 (m, 15H). MS (ESI+) m/z 387 (M+H)⁺.

Example 33D((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)aceticacid

To a solution of the product of Example 33C (40 mg, 0.1 mmol) inethylene glycol (0.5 ml) was added 25% KOH solution (0.2 ml). Thereaction mixture was heated to 150° C. overnight and concentrated. Theresidue was purified by reverse phase preparative HPLC on a WatersSymmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradientof 10% to 100% acetonitrile:0.1% aqueous TFA over 8 min (10 min runtime) at a flow rate of 40 mL/min. to provide the title compound (19 mg,45%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.19-7.25 (m, 2H), 6.96-7.02 (m,1H), 6.82-6.90 (m, 2H), 3.98-4.07 (m, 1H), 2.11-2.18 (m, 2H), 1.88-2.03(m, 3H), 1.47-1.85 (m, 16H). MS (ESI+) m/z 406 (M+H)⁺.

Example 34N-[(E)-5-(2-Amino-2-oxocthyl)-2-adamantyl]-2-(4-chlorophenoxy)-2-methylpropanamide

To a solution of the product of Example 33C (22 mg, 0.057 mmol) in MeOH(0.15 ml)/DMSO (0.005 ml) were added 30% H₂O₂ (0.011 ml) and 0.2 M NaOH(0.006 ml). The reaction mixture was heated to 50° C. overnight andconcentrated. The residue was purified by reverse phase preparative HPLCon a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) usinga gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8 min (10min run time) at a flow rate of 40 mL/min. to provide the title compound(13 mg, 56%).

¹H NMR (500 MHz, CDCl₃) δ ppm 7.21-7.26 (m, 2H), 6.94-7.04 (m, 1H),6.84-6.91 (m, 2H), 5.62-5.72 (m, 1H), 5.35-5.43 (m, 1H), 3.97-4.06 (m,1H), 1.89-2.05 (m, 5H), 1.48-1.80 (m, 18H). MS (ESI+) m/z 405 (M+H)⁺.

Example 352-(4-Chlorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-ylmethyl)-2-adamantyl]propanamide

To a solution of the product of Example 33C (65 mg, 0.168 mmol) in water(0.2 ml)/isopropanol (0.1 ml) were added NaN₃ (22 mg, 0.337 mmol) andZnBr₂ (19 mg, 0.084 mmol). The reaction mixture was heated to 150° C. ina sealed tube for two days and concentrated. The residue was purified byreverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:0.1% aqueous TFA over 8 min (10 min run time) at a flowrate of 40 mL/min. to provide the title compound (43 mg, 45%). ¹H NMR(400 MHz, CD₃OD) δ ppm 7.34-7.43 (m, 1H), 7.23-7.31 (m, 2H), 6.89-6.96(m, 2H), 3.84-3.92 (m, 1H), 2.75 (s, 2H), 1.86-2.02 (m, 3H), 1.43-1.74(m, 16H). MS (ESI+) m/z 430 (M+H)⁺.

Example 36N-{(E)-5-[(Aminosulfonyl)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamideExample 36AN-{(E)-5-[(Thioacetyl)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide

To a 0° C. solution of the product of Example 33A (0.71 g, 1.88 mmol) inCH₂Cl₂ (5.0 mL) and pyridine (0.46 mL, 5.64 mmol) was addedtrifluoromethanesulfonic anhydride (0.35 mL, 2.07 mmol). The reactionmixture was stirred under an atmosphere of N₂ for 30 min at 0° C. Thecrude products were diluted with EtOAc, washed with water and brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. The resultingcrude material was dissolved in DMF (5.0 mL), treated with potassiumthioacetate (0.43 g, 3.76 mmol), and heated to 70° C. overnight. Thecrude reaction mixture was diluted with EtOAc, washed with water (3×)and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography employing asolvent gradient (hexane-60:40 hexane:EtOAc) to yield the title compound(0.74 g, 90%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.23 (d,J=8.82 Hz, 2H), 6.95 (m, 1H), 6.86 (d, J=8.82 Hz, 2H), 3.98 (m, 1H),2.76 (s, 2H), 2.35 (s, 3H), 1.89-1.97 (m, 3H) 1.45-1.68 (m, 10H), 1.50(s, 6H). MS (ESI+) m/z 436 (M+H)⁺.

Example 36B N-{(E)-5-[(Sulfonicacid)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide

To a solution of the product of Example 36A (0.74 g, 1.70 mmol) andNaOAc (0.1392 g, 1.70 mmol) in acetic acid (10 mL) was added 30%hydrogen peroxide in water (1.6 mL, 15.3 mmol). The reaction solutionwas stirred at room temperature overnight and excess peroxide quenchedby adding dimethylsulfide (1.9 mL, 25.5 mmol) and stirring for 2 h. Thereaction solution was concentrated under reduced pressure to provide thecrude product as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.22 (d,J=8.85 Hz, 2H), 7.07 (d, J=7.94 Hz, 1H), 6.86 (d, J=8.85 Hz, 2H), 3.95(m, 1H), 2.80 (s, 2H), 1.51-2.17 (m, 13H) 1.46 (s, 6H). MS (ESI+) m/z442 (M+H)⁺.

Example 36CN-{(E)-5-[(Aminosulfonyl)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide

To a solution of the product of Example 36B (55.8 mg, 0.126 mmol) in DCM(1.2 mL) and DMF (1 drop) was added triphosgene (27.4 mg, 0.0922 mmol)and triethylamine (0.018 mL, 0.126 mmol). The resulting reaction mixturewas stirred at room temperature for 2 hours and ammonia (0.5 M indioxane, 2.5 mL, 1.26 mmol) was added. After stirring for 2 h at roomtemperature the reaction was quenched with water and extracted withEtOAc. The organic layer was then rinsed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified byreverse phase preparative HPLC using acetonitrile: 10 mM NH₄OAc on YMCGuardpak column to provide the title compound (20 mg, 36%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.24 (d, J=8.9 Hz, 2H), 6.98 (d,J=8.28 Hz, 1H), 6.86 (d, J=8.9 Hz, 2H), 4.79 (s, 2H), 4.04 (m, 1H), 3.04(s, 2H), 1.87-2.04 (m, 8H), 1.54-1.66 (m, 5H), 1.50 (s, 6H). MS (ESI+)m/z 441 (M+H)⁺.

Example 37N-{(E)-5-[(Z)-Amino(hydroxyimino)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamideExample 37A (5-Carbamoyl-adamantan-2-yl)-carbamic acid benzyl ester StepA

CbzCl (3.48 mL, 24.72 mmol) was added dropwise to a stirred and cooled(0° C.) solution of the product of Example 7B (5.05 g, 20.60 mmol) andDIPEA (7.9 mL, 45.32 mmol) in dry CH₂Cl₂ (100 mL). After the addition,the solution was allowed to warm to room temperature and stirred foranother 2 hrs. Saturated NaHCO₃ solution was added to quench thereaction and the phases were separated. The organic phase was washedwith NaHSO₄ solution, NaHCO₃ solution, dried (Na₂SO₄), filtered, andconcentrated. The residue was purified over silica gel using 20% EtOAcin hexanes and concentrated.

Step B

The product of step A (6.49 g, 18.91 mmol) was dissolved in dry THF (90mL) and KOTMS (4.85 g, 37.82 mmol) was added at room temperature. Theresulting solution was stirred overnight before water (100 mL) and Et₂O(100 mL) were added and the phases were separated. The aqueous phase wasacidified using solid NaHSO₄ until pH 1 was reached. The aqueous phasewas then extracted using EtOAc. The combined organic extract was dried(MgSO₄), filtered, and concentrated.

Step C

The product of Step B (18.91 mmol) was dissolved in dry CH₂Cl₂ (60 mL)and DIPEA (10 mL, 56.7 mmol), HOBt (5.1 g, 37.82 mmol), and EDCI (5.4 g,28.36 mmol) were added to the solution. The resulting mixture wasstirred for 1 h before NH₃ (30 mL, 2 M in iPrOH, 56.7 mmol) was added.After 1 h of stirring at 25° C., the solution was diluted with CH₂Cl₂(200 mL) and washed with NaHSO₄ solution, 1 M NaOH, water, dried(Na₂SO₄) and filtered. The residue was purified over silica gel using 5%MeOH in CH₂Cl₂ to provide the title compound as a solid.

Example 37B E-4-Amino-adamantane-1-carbonitrile Step A

The product of Step C of Example 37A, 18.91 mmol) was dissolved in dryCH₂Cl₂ (60 mL) and Et₃N (10.5 mL, 75.64 mmol). TFAA (7.9 mL, 56.73 mmol)was added dropwise to the solution at 0° C. After the addition, thesolution was allowed to warm to room temperature and stirred for 3 hoursbefore MeOH was added to quench the reaction. The solution was washedwith NaHSO₄ solution, NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated. The residue was purified over silica gel using 30% EtOAcin hexanes and concentrated to yield an oil.

Step B

Pd(OH)₂/C (0.9 g) was added to a solution of the product of Step A (3.22g, 10.38 mmol). The solution was stirred at room temperature under H₂(balloon) until starting material was consumed. The mixture was filteredthrough a pad of Celite and concentrated in vacuo to provide the titlecompound as a solid.

Example 37C2-(4-Chloro-phenoxy)-N-[(E)-5-(N-hydroxycarbamimidoyl)-adamantan-2-yl]-2-methyl-propionamideStep A

HATU (0.64 g, 1.67 mmol) was added in one portion to a stirred solutionof 2-(4-chloro-phenoxy)-2-methyl-propionic acid (0.3 g, 1.50 mmol) andthe product of Step B of Example 37B (0.27 g, 1.53 mmol), and DIPEA(0.73 mL, 4.2 mmol) in dry DMF (7 mL). The reaction was allowed to stirfor 5 hours before it was diluted with CH₂Cl₂ and washed with NaHSO₄solution, 1M NaOH, brine, and dried (Na₂SO₄), and evaporated. Theresidue was purified over silica gel using 20% EtOAc/hexanes andconcentrated to yield a white solid.

Step B

To the product of Step A (87 mg, 0.209 mmol) was added NH₃OHCl (87 mg,1.25 mmol), DIPEA (0.29 mL, 1.67 mmol) and dry DMSO (1 mL). Theresulting solution was heated at 80° C. for 8 hrs. The solvent wasevaporated and the residue was purified on HPLC using CH₃CN/water 1% TFAas eluent to provide the title compound as an oil. ¹H NMR (300 MHz,CD₃OD) δ ppm 7.49-7.54 (m, 1H), 7.26-7.30 (m, 2H), 6.92-6.96 (m, 2H),3.97-4.03 (m, 1H), 2.10-2.15 (m, 2H), 1.98-2.08 (m, 5H), 1.92-1.94 (m,2H), 1.76-1.83 (m, 2H), 1.57-1.64 (m, 2H), 1.53 (s, 6H). MS (ESI+) m/z406.1 (M+H)⁺.

Example 38E-N-[4-(Aminosulfonyl)benzyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 24, substituting 4-aminomethyl-benzenesulfonamide hydrochloridefor 4-aminomethyl-benzoic acid methyl ester hydrochloride. ¹H NMR (500MHz, DMSO-d₆) δ ppm 8.10-8.15 (m, 1H), 7.75 (d, J=8.08 Hz, 2H), 7.37 (d,J=8.03 Hz, 2H), 7.31-7.35 (m, 3H), 7.29-7.29 (bs, 2H), 6.91-6.93 (m,2H), 4.30 (d, J=5.87 Hz, 2H), 3.84-3.88 (m, 1H), 1.93-1.95 (m, 2H),1.82-1.92 (m, 5H), 1.76-1.78 (m, 2H), 1.67-1.71 (m, 2H), 1.46 (s, 6H),1.37-1.41 (m, 2H). MS (ESI+) m/z 560 (M+H)⁺.

Example 39E-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-N-(4-{[methylsulfonyl)amino]carbonyl}benzyl)adamantane-1-carboxamide

To a solution of the product of Example 24 (26 mg, 0.05 mmol) in DMF (1mL) were added DMAP (7 mg, 0.055 mmol), EDCI (12 mg, 0.06 mmol) andmethylsulfonamide (7 mg, 0.075 mmol). The reaction mixture was stirredat room temperature for 72 hours, concentrated in vacuo, and the residuewas purified by reverse phase preparative HPLC on a Waters Symmetry C8column (25 mm×100 mm, 7 um particle size) using a gradient of 10% to100% acetonitrile:0.1% aqueous TFA over 8 min (10 min run time) at aflow rate of 40 mL/min. to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.01-12.05 (bs, 1H), 8.11 (t, J=6.06 Hz, 1H), 7.87 (d,J=8.19 Hz, 2H), 7.30-7.37 (m, 5H), 6.91-6.93 (m, 2H), 4.31 (d, J=5.89Hz, 2H), 3.83-3.87 (m, 1H), 3.36 (s, 3H), 1.82-1.96 (m, 7H), 1.77-1.79(m, 2H), 1.67-1.72 (m, 2H), 1.47 (s, 6H), 1.37-1.42 (m, 2H). MS (ESI+)m/z 602 (M+H)⁺.

Example 40E-4-({2-[(4-Chlorophenyl)thio]-2-methylpropanoyl}amino)adamantane-1-carboxylicacid Example 40A

Example 40A was prepared according to the procedure outlined in Example25A, substituting 4-chloro-benzenethiol for 2,3-dimethylphenol.

Example 40BE-4-({2-[(4-Chlorophenyl)thio]-2-methylpropanoyl}amino)adamantane-1-carboxylicacid

The title compound was prepared according to the procedure outlined inExample 25B, substituting the product of Example 40A for the product ofExample 25A. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.42-7.45 (m, 2H),7.36-7.39 (m, 2H), 7.11-7.21 (m, 1H), 3.72-3.78 (m, 1H), 1.91-1.94 (m,2H), 1.79-1.92 (m, 6H), 1.75-1.80 (m, 3H), 1.44 (s, 8H). MS (ESI+) m/z408 (M+H)⁺.

Example 41E-4-({2-[(4-Methoxyphenyl)thio]-2-methylpropanoyl}amino)adamantane-1-carboxamideamide Example 41AE-4-(2-Bromo-2-methyl-propionylamino)-adamantane-1-carboxylic acid

A solution of the product of Example 1B (0.78 g, 2.48 mmol) in 99%formic acid (2.5 mL) was added dropwise with vigorous gas evolution over10 minutes to a rapidly stirred 30% oleum solution (7.5 mL) heated to60° C. (W. J. le Noble, S. Srivastava, C. K. Cheung, J. Org. Chem. 48:1099-1101, 1983). Upon completion of addition, more 99% formic acid (2.5mL) was slowly added over the next 10 minutes. The mixture was stirredfor another 60 minutes at 60° C. and then slowly poured into vigorouslystirred iced water (30.0 mL) cooled to 0° C. The mixture was allowed toslowly warm to 23° C., filtered and washed with water to neutral pH (100mL). The precipitate was dried in a vacuum oven overnight to provide thetitle compound.

Example 41BE-4-(2-Bromo-2-methyl-propionylamino)-adamantane-1-carboxylic acid amide

A solution of the product of Example 41A (250 mg, 0.670 mmol) in DCM (30mL) was treated with HOBt (109 mg, 0.80 mmol) and EDCI (154 mg, 0.80mmol) and stirred at room temperature for 3 hour. Excess of aqueous(30%) ammonia (20 mL) was added and the reaction was stirred foradditional 20 hours. The layers were separated and the aqueous layerextracted twice more with methylene chloride (2×40 mL). The combinedorganic extracts were washed with water (3×20 mL) and brine (20 mL);dried (MgSO₄) and filtered. The filtrate was concentrated under reducedpressure to provide the crude title compound that was purified by normalphase column chromatography (silica gel, 5% methanol in DCM) to affordthe title compound. MS (ESI+) m/z 343 (M+H)⁺.

Example 41CE-4-[2-(4-Methoxy-phenylsulfanyl)-2-methyl-propionylamino]-adamantane-1-carboxylicacid amide

A solution of 4-methoxy-benzenethiol (44 mg, 0.31 mmol) and sodiumhydride (60%, 15.0 mg, 0.37 mmol) in toluene (4 mL) was stirred at roomtemperature for 1 hour. The product of Example 41B (106.0 mg, 0.31 mmol)was added to the solution and the resulting mixture was stirred at 100°C. for 24 hours. The reaction mixture was cooled and filtered. Thefiltrate was concentrated under reduced pressure to provide crudeproduct that was purified by reverse phase preparative HPLC on a WatersSymmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradientof 10% to 100% acetonitrile:0.1% aqueous TFA over 8 min (10 min runtime) at a flow rate of 40 mL/min. to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 7.33-7.35 (m, 2H), 7.11 (d, J=7.18 Hz, 1H),6.99-7.01 (s, 1H), 6.93-6.95 (m, 2H), 6.72-6.74 (s, 1H), 3.75-3.79 (m,1H), 3.77 (s, 3H), 1.79-1.95 (m, 9H), 1.75-1.77 (m, 2H), 1.44-1.48 (m,2H), 1.39 (s, 6H). MS (ESI+) m/z 403 (M+H)⁺.

Example 42E-4-({2-[(4-Methoxyphenyl)sulfinyl]-2-methylpropanoyl}amino)adamantane-1-carboxamide

A solution of the product of Example 41C (53 mg, 0.087 mmol) in methanol(5 mL) was treated with OXONE (80 mg, 0.130 mmol) and stirred at roomtemperature for 7 hours. The reaction mixture was filtered. The filtratewas concentrated under reduced pressure to provide crude title compoundthat was subsequently purified by reverse phase preparative HPLC on YMCGuardpak column using a gradient of 0% to 70% acetonitrile:0.1% aqueousTFA over 8 min (10 min run time) at a flow rate of 40 mL/min. to affordthe title compound. ¹H NMR (400 MHz, DMSO-d) δ ppm 7.49-7.52 (m, 2H),7.32 (d, J=6.93 Hz, 1H), 7.09-7.12 (m, 2H), 6.96-6.99 (s, 1H), 6.68-6.71(s, 1H), 3.82 (s, 3H), 3.75-3.81 (m, 1H), 1.89-1.92 (m, 3H), 1.73-1.86(m, 8H), 1.42-1.51 (m, 2H), 1.34 (s, 3H), 1.25 (s, 3H). MS (ESI+) m/z419 (M+H)⁺.

Example 43E-4-({2-[(4-Methoxyphenyl)sulfonyl]-2-methylpropanoyl}amino)adamantane-1-carboxamide

A solution of the product of Example 41C (53 mg, 0.087 mmol) in methanol(5 mL) was treated with OXONE (80 mg, 0.130 mmol) and stirred at roomtemperature for 24 hour. The reaction mixture was filtered. The filtratewas concentrated under reduced pressure to provide crude title compoundthat was subsequently purified by reverse phase preparative HPLC on aWaters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using agradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8 min (10 minrun time) at a flow rate of 40 mL/min. to afford the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.72 (d, J=8.65 Hz, 2H), 7.17-7.20 (m, 3H),6.97-6.99 (s, 1H), 6.70-6.72 (s, 1H), 3.88 (s, 3H), 3.77-3.83 (m, 1H),1.94-1.97 (m, 3H), 1.82-1.89 (m, 6H), 1.76-1.78 (m, 2H), 1.49-1.54 (m,2H), 1.45 (s, 6H). MS (ESI+) m/z 435 (M+H)⁺.

Example 44E-4-({2-[4-Chloro-2-(pyrrolidin-1-ylsulfonyl)phenoxy]-2-methylpropanoyl}aminoadamantane-1-carboxamideExample 44A 2-Hydroxy-5-chlorobenzene sulfonyl chloride

4-Chlorophenol (4 g, 31.25 mmol) was added in portions to chlorosulfonicacid (10.3 mL, 156 mmol) while cooling in an ice bath. The resultingsolution was stirred at 25° C. for 20 hrs. This was then added drop-wiseto ice and water resulting in an emulsion. This was extracted withCHCl₃, dried (Na₂SO₄) and concentrated in vacuo. Heptane was added andevaporated and replaced with cyclohexane. The resulting mixture wasfiltered and concentrated to give the title compound as an oil (2.16 g).

Example 44B 2-Hydroxy-5-chlorobenzene sulfonyl pyrrolidine

To a solution of the product of Example 44A (2.16 g, 9.51 mmol) in CHCl₃(8 mL) was added, with ice cooling, pyrrolidine (4.05 g, 57.04 mmol).The mixture was stirred at 25° C. for 2 hrs, then concentrated in vacuo.The residue was dissolved in toluene, washed with HCl and water, dried(Na₂SO₄) and concentrated. The resulting oil was crystallized fromhexane and chromatographed (CH₂Cl₂) to yield the title compound (1.92g), m.p. 101-102° C.

Example 44C2-[4-Chloro-2-(pyrrolidine-1-sulfonyl)-phenoxy]-2-methyl-propionic acid

The product of Example 44B (1.0 g, 3.82 mmol) and1,1,1-trichloro-2-methyl-2-propanol hydrate (1.832 g, 10.32 mmol) weredissolved in acetone (8.5 mL). Powdered NaOH (0.47 g. 11.75 mmol) wasadded with cooling. The resulting mixture was stirred for 1.5 hr at 25°C. A second batch of powdered NaOH (0.47 g) was added and stirred foranother 1.5 hrs. The last batch of powdered NaOH (0.47 g) was then addedalong with acetone (2.5 mL). The resulting mixture was stirred for 15hrs at 25° C. Acetone was added and the solution was filtered. Theresulting solution was concentrated. Water (3 mL) was added andconcentrated HCl was added to acidify the mixture, which was extractedwith toluene, dried and concentrated. The residue was chromatographed onsilica gel. Eluting with CH₂Cl₂ gave 380 mg recovered starting material.Changing to 5% MeOH in ethyl acetate gave the title compound (357 mg,27% yield).

Example 44DE-4-({2-[4-Chloro-2-(pyrrolidin-1-ylsulfonyl)phenoxy]-2-methylpropanoyl}amino)adamantane-1-carboxamide

The product of Example 7B (75 mg, 0.305 mmol), the product of Example44C (116 mg, 0.335 mmol), and TBTU (108 mg, 0.336 mmol) were suspendedin dimethylacetamide (0.5 mL). Diisopropylethylamine (135 mg, 1.05 mmol)was added and the resulting solution stirred at 25° C. for 15 hrs.Toluene was added, and concentrated. More toluene was added, and washedwith dil H₃PO₄, H₂O, and then KHCO₃. The organic phase was dried(Na₂SO₄), and filtered. The solvents were removed in vacuo and theresidue crystallized from ether and heptane to yield the title compound(133 mg), m.p. 152-154° C.

Example 44EE-4-{2-[4-Chloro-2-(pyrrolidine-1-sulfonyl)-phenoxy]-2-methyl-propionylamino}-adamantane-1-carboxylicacid

A solution of the product of Example 44D (125 mg, 0.231 mmol) in MeOH(0.75 mL) was treated with NaOH (100 mg) in water (0.5 mL). The mixturewas heated until all was soluble and stirred at 60° C. for 1 hour. Thesolvent was removed in vacuo and the residue acidified with HCl,extracted with CHCl₃, dried (Na₂SO₄), filtered, and concentrated. Theresidue was crystallized from ether to yield the title compound (92 mg,77% yield), m.p. 226-228° C.

Example 44FE-4-({2-[4-Chloro-2-(pyrrolidin-1-ylsulfonyl)phenoxy]-2-methylpropanoyl}amino)adamantane-1-carboxamide

The product of Example 44E (76 mg, 0.145 mmol), TBTU (52 mg, 0.162mmol), and diisopropylethylamine (40 mg, 0.31 mmol) were dissolved inN,N-dimethylacetamide (0.3 mL). After 25 min. at 25° C., a solution of10% ammonia in THF was added. A solid formed and the mixture was stirredfor 3 hrs at 25° C. Toluene was added and the mixture concentrated invacuo. The residue was dissolved in CHCl₃ and washed with dil H₃PO₄,H₂O, and KHCO₃; dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was crystallized from ether to yield the title compound (64 mg,m.p. 249-252° C.). ¹H NMR (400 MHz, CDCl₃) 5 ppm 7.85 (d, J=2 Hz, 1H),7.37 (dd, J=2, 9 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 7.05 (d, J=9 Hz, 1H),5.62 (br s 1H), 5.40 (br s, 1H), 3.96 (d, J=8 Hz, 1H), 3.38-3.46 (m,4H), 1.81-2.03, (m, 9H), 1.86-1.94 (m, 4H), 1.76 (s, 6H), 1.63 (d, J=12Hz, 2H), 1.44 (d, J=12 Hz, 2H). MS (ESI+) m/z 524, 526 (M+H)⁺.

Example 45E-4-({2-Methyl-2-[4-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamideExample 45A

Example 45A was prepared according to the procedure outlined in Example44C, substituting 4-(methanesulfonyl)-phenol for the product of Example44B.

Example 45B

Example 45B was prepared according to the procedure outlined in Example44D, substituting the product of Example 45A for the product of Example44C.

Example 45C

Example 45C was prepared according to the procedure outlined in Example44E, substituting the product of Example 45B for the product of Example44D.

Example 45DE-4-({2-Methyl-2-[4-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 44F, substituting the product of Example 45C for the product ofExample 44E. The product had m.p. 217-219° C. ¹H NMR (500 MHz, CDCl₃) 5ppm 7.85 (d, J=8 Hz, 2H), 7.05 (d, J=8 Hz, 2H), 6.66 (d, J=7 Hz, 1H),5.65 (br s, 1H), 5.49 (br s 1H), 4.06 (d, J=7 Hz, 1H), 3.05 (s, 3H),1.86-2.10 (m, 9H), 1.62 (s, 6H), 1.52 (s, 4H). MS (ESI+) m/z 435 (M+H)⁺.

Example 46E-4-({2-Methyl-2-[2-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamideExample 46A 2-Methyl-2-(2-methylsulfanyl-phenoxy)-propionic acid, ethylester

2-Methylsulfanyl-phenol (2.00 g, 14.29 mmol), 2-bromo-2-methyl-propionicacid, ethyl ester (28 g, 142.8 mmol) and powdered K₂CO₃ (4.93 g, 35.7mmol) were mixed (no solvent) and stirred at 105° C. for 8 hrs. Aftercooling, water and CHCl₃ were added. The CHCl₃ was separated, dried(MgSO₄) and concentrated. Xylene was added and concentrated in vacuo (4times) to remove the bromo ester. The resulting oil was chromatographedon silica, eluting with CH₂Cl₂ to obtain the title compound (2.30 g, 63%yield).

Example 46B 2-Methyl-2-(2-methanesulfonyl-phenoxy)-propionic acid, ethylester

To the product of Example 46A (1.00 g, 3.93 mmol) in CH₂Cl₂ (15 mL), wasadded, in portions, 3-chloroperoxybenzoic acid (3.00 g of 70%, 12.16mmol) while stirring and cooling in a water bath. The mixture wasstirred at 25° C. for 20 hrs. Chloroform was added and the mixture waswashed with KHCO₃, Na₂S₂O₃, and again with KHCO₃. The solution was dried(Na₂SO₄), filtered and concentrated. Heptane was added and concentratedto obtain an oil that solidified (1.22 g, theory=1.142 g).

Example 46C 2-Methyl-2-(2-methanesulfonyl-phenoxy)-propionic acid

The product of Example 46B (1.22 g) was dissolved in MeOH (8 mL) andtreated with 50% NaOH (1.75 g, 21.27 mmol) and water (6 mL). The mixturewas heated until all was soluble and stirred at 25° C. for 1 hr. Thesolvents were removed in vacuo, water (6 mL) was added and the solutionacidified with HCl. The mixture was extracted with CHCl₃, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue wascrystallized from ether and heptane (1:4) to yield the title compound(0.953 g), m.p. 114-116° C.

Example 46D

Example 46D was prepared according to the procedure outlined in Example44D substituting the product of Example 46C for the product of Example44C.

Example 46E

Example 46E was prepared according to the procedures outlined in Example44E substituting the product of Example 46D for the product of Example44D.

Example 46FE-4-({2-Methyl-2-[2-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 44F, substituting the product of Example 46E for the product ofExample 44E. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.99 (dd, J=7, 2 Hz, 1H),7.53 (m, 1H), 7.10-7.16 (m, 2H), 5.60 (br s 1H), 5.40 (br s, 1H), 3.95(d, J=8 Hz, 1H), 3.27 (s, 3H), 1.80-1.96 (m, 9H), 1.55 (d, J=12 Hz, 2H),1.37 (d, J=12 Hz, 2H). MS (ESI+) m/z 435 (M+H)⁺.

Example 47E-4-[(2-{4-Chloro-2-[(diethylamino)sulfonyl]phenoxy}-2-methylpropanoyl)amino]adamantane-1-carboxamideExample 47A

Example 47A was prepared according to the procedure outlined in Example44B, substituting diethylamine for pyrrolidine.

Example 47B

Example 47B was prepared according to the procedure outlined in Example44C, substituting the product of Example 47A for the product of Example44B.

Example 47C

Example 47C was prepared according to the procedure outlined in Example44D, substituting the product of Example 47B for the product of Example44C.

Example 47D

Example 47D was prepared according to the procedure outlined in Example44E, substituting the product of Example 47C for the product of Example44D.

Example 47EE-4-[(2-{4-Chloro-2-[(diethylamino)sulfonyl]phenoxy}-2-methylpropanoyl)amino]adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 44F, substituting the product of Example 47D for the product ofExample 44E. The compound had m.p. 159-161° C. ¹H NMR (400 MHz, CDCl₃) δppm 7.83 (d, J=2 Hz, 1H), 7.34 (dd, J=2, 9 Hz, 1H), 7.05 (d, J=8 Hz,1H), 6.98 (d, J=9 Hz, 1H), 5.58 (br s 1H), 5.38 (br s, 1H), 3.95 (d, J=8Hz, 1H), 3.40 (q, J=7 Hz, 4H), 1.81-1.98, (m, 9H), 1.75 (s, 6H), 1.56(d, J=12 Hz, 2H), 1.42 (d, J=12 Hz, 2H), 1.17 (t, J=7 Hz, 6H). MS (ESI+)m/z 526, 528 (M+H)⁺.

Example 48E-4-({2-Methyl-2-[4-(pyrrolidin-1-ylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamideExample 48A 1-(4-Methoxy-benzenesulfonyl)-pyrrolidine

4-Methoxy-benzenesulfonyl chloride (3.00 g, 14.52 mmol) was slowly addedto a solution of pyrrolidine (5.15 g, 72.6 mmol) in CHCl₃ (15 mL) withstirring at 0° C. The reaction mixture was allowed to warm up to roomtemperature and then stirred for 1 hour. After that the reaction mixturewas concentrated in vacuo. The residue was dissolved in toluene andwashed with aqueous H₃PO₄ solution, and then aqueous KHCO₃ solution. Theorganic phase was dried with Na₂SO₄, and filtered. The solvents wereremoved in vacuo and the residue crystallized from ether and heptane toprovide the title compound (3.21 g, m.p. 88-89° C.).

Example 48B 1-(4-Hydroxy-benzenesulfonyl)-pyrrolidine

The product of Example 48A (3.21 g, 13.3 mmol) was dissolved in CH₂Cl₂(30 mL), cooled to −78° C. and treated with BBr₃ (8.31 g, 3.26 mmol).The resulting dark red solution was stirred at 25° C. for 4 min, thencooled to −78° C. Methanol (100 mL) was added slowly. The solution wasconcentrated in vacuo. Toluene was added to the crude and concentratedagain. After adding more toluene, the solution was washed with water andconcentrated in vacuo. The residue was dissolved in ether and extractedwith NaOH (1.0 g) in water (8 mL). The aqueous layer was removed andstirred 15 minutes, then acidified with concentrated HCl. This mixturewas extracted with toluene, dried (Na₂SO₄), filtered, concentrated invacuo and the residue crystallized from ether and heptane (2:1) toprovide the title compound (1.063 g, m.p. 122-125° C.).

Example 48C

Example 48C was prepared according to the procedure outlined in Example44C, substituting the product of Example 48B for the product of Example44B.

Example 48D

Example 48D was prepared according to the procedure outlined in Example44D, substituting the product of Example 48C for the product of Example44C.

Example 48E

Example 48E was prepared according to the procedure outlined in Example44E, substituting the product of Example 48D for the product of Example44D.

Example 48FE-4-({2-Methyl-2-[4-(pyrrolidin-1-ylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the procedure outlined inExample 44F, substituting the product of Example 48E for the product ofExample 44E. The compound had m.p. 206-209° C. ¹H NMR (500 MHz, CDCl₃) δppm 7.76 (d, J=8 Hz, 2H), 7.02 (d, J=8 Hz, 2H), 6.71 (d, J=8 Hz, 1H),5.65 (br s, 1H), 5.54 (br s, 1H), 4.067 (d, J=8 Hz, 1H), 3.20-3.26 (m,4H), 1.86-2.06 (m, 9H), 1.77-1.82 (m, 4H), 1.61 (s, 6H), 1.51 (s, 4H).MS (ESI+) m/z 490 (M+H)⁺.

Example 492-(2-Chloro-4-fluorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamideExample 49A 2-(4-Fluoro-2-chlorophenoxy)-2-methyl-propionic acid

4-Fluoro-2-chlorophenol (6.00 g, 41.1 mmol) was reacted with1,1,1-trichloro-2-methyl-2-propanol hydrate (120 g, 12.70 mmol) asdescribed in Example 44C to provide the title compound (6.075 g, 64%yield, m.p. 63-65° C.).

Example 49B2-(2-Chloro-4-fluorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamide

The product of Example 1A (175 mg, 1.05 mmol),2-(4-fluoro-2-chlorophenoxy)-2-methyl-propionic acid (232 mg, 1.00mmol), and TBTU (353 mg, 1.1 mmol) were dissolved inN,N-dimethylacetamide. Di-isopropylethylamine (258 mg, 2.0 mmol) wasadded and the mixture was stirred for 18 hrs at 25° C. After that thereaction mixture was concentrated in vacuo. The residue was dissolved intoluene and washed with aqueous H₃PO₄ solution, and then aqueous KHCO₃solution. The organic phase was dried with Na₂SO₄, and filtered. Thesolvents were removed in vacuo and the residue crystallized from etherand heptane to provide the title compound (262 mg, m.p. 177-179° C.). ¹HNMR (500 MHz, CDCl₃) δ ppm 7.47 (d, J=8 Hz, 1H), 7.18 (dd, J=2, 8 Hz,1H), 7.08 (dd, J=5 Hz, 8 Hz, 1H), 6.94 (m, 1H), 4.07 (d, J=8 Hz, 1H),2.12-2.21 (m, 3H), 1.91 (d, J=11 Hz, 2H), 1.70-1.84 (m, 6H), 1.43-1.65(m, 3H), 1.53 (s, 6H). MS (ESI+) m/z 382, 384 (M+H)⁺.

Example 502-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2-adamantyl]propanamideExample 50A

Example 50A was prepared according to the procedure outlined in Example44D, substituting the product of Example 49A for the product of Example44C.

Example 50B

Example 50B was prepared according to the procedure outlined in Example44E, substituting the product of Example 50A for the product of Example44D.

Example 50CE-4-[2-(2-Chloro-4-fluorophenoxy)-2-methyl-propionylamino]-adamantane-1-carbonitrileStep A

E-4-[2-(2-Chloro-4-fluoro-phenoxy)-2-methyl-propionylamino]-adamantane-1-carboxylicacid amide was prepared according to the procedure outlined in Example44F, substituting the product of Example 50B for the product of Example44E.

Step B

The solution of the product of Step A (207 mg, 0.506 mmol) in dioxane(0.5 mL) and pyridine (100 mg) was treated with trifluoroaceticanhydride (167 mg, 0.795 mmol). The mixture was stirred 5 hr at 25° C.and concentrated in vacuo after adding toluene. More toluene was addedand the solution was washed with dilute H₃PO₄, water, and aqueous KHCO₃solution respectively. After drying with Na₂SO₄, the solution wasfiltered, concentrated in vacuo and the residue crystallized from etherand heptane to yield the title compound (115 mg, m.p. 159-160° C.).

Example 50D2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2-adamantyl]propanamide

A solution of the product of step B of Example 50C (50 mg, 0.128 mmol),trimethyltin chloride (31 mg, 0.153 mmol) and NaN₃ (10 mg, 0.153 mmol)in toluene (0.3 mL) was stirred and heated for 64 hrs in a sealed vialat 120° C. The mixture was cooled and 4N HCl in dioxane (1 mL) wasadded. After stirring 90 min at 25° C. the solution was concentrated invacuo. Water and HCl were added and the mixture was extracted withCHCl₃, dried with Na₂SO₄, filtered, concentrated and treated with etherto provide the title compound (33 mg, m.p. 256-257° C.). ¹H NMR (400MHz, DMSO-d) δ ppm 7.52 (d, J=8 Hz, 1H), 7.15-7.23 (m, 2H), 3.98 (d, J=8Hz 1H), 1.98-2.12 (m, 9H), 1.90 (d, J=13 Hz, 2H), 1.60 (d, J=13 Hz, 2H),1.46 (s, 6H). MS (ESI+) m/z 434, 435 (M+H)⁺.

Example 512-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylthio)-2-adamantyl]propanamide

A solution of the product of Example 49B (150 mg, 0.392 mmol) in CF₃COOH(750 mg) was treated with trifluoroacetic anhydride (375 mg, 1.78 mmol)for 5 min. Then, CF₃COOH (1.68 g, 14.9 mmol) and NaSCH₃ (549 mg, 7.8mmols) were added to the 7 mL sealed tube. This mixture was heated at120° C. for 20 hrs. After cooling, toluene was added, and the mixtureconcentrated in vacuo. More toluene was added and this was shaken withK₂CO₃ solution. The toluene layer was separated, dried (Na₂SO₄),concentrated and chromatographed in 4% EtOAc in DCM to give the titlecompound (132 mg, m.p. 100-101° C.). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.50(d, J=8 Hz, 1H), 7.17 (dd, J=2, 8 Hz, 1H), 7.08 (dd, J=5, 8 Hz, 1H),6.93 (m, 1H), 4.07 (d, J=8 Hz, 1H), 1.82-2.15 (m, 9H), 2.03 (s, 3H),1.82 (d, J=13 Hz, 2H), 1.59 (d, J=13 Hz, 2H), 1.54 (s, 6H), MS (ESI+)m/z 412, 414 (M+H)⁺.

Example 522-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylsulfonyl)-2-adamantyl]propanamide

A solution of the product of Example 51 (100 mg, 0.235 mmol) in CH₂Cl₂(1 ml) was treated with 3-chloroperbenzoic acid (180 mg, 70%, 1.05mmol). After stirring for 17 hrs at 25° C., CHCl₃ was added to thereaction mixture and the solution was extracted with KHCO₃, Na₂S₂O₃, andKHCO₃. After drying (Na₂SO₄), filtered and concentrating, the residuewas crystallized from heptane and ether to provide the title compound(89 mg, m.p. 172-173° C.). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.55 (d, J=8Hz, 1H), 7.18 (dd, J=2, 8 Hz, 1H), 7.09 (dd, J=5, 8 Hz, 1H), 6.95 (m,1H), 4.09 (d, J=8 Hz, 1H), 2.76 (s, 3H), 2.07-2.25 (m, 9H), 1.90 (d,J=13 Hz, 2H), 1.65 (d, J=13 Hz, 2H), 1.54 (s, 6H). MS (ESI+) m/z 444,446 (M+H)⁺.

Example 532-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylsulfinyl)-2-adamantyl]propanamide

A-solution of the product of Example 51 (71 mg, 0.172 mmol) in aceticacid (75 mL) was prepared. Sodium perborate (NaBO₃.H₂O, 18 mg, 0.18mmol) was added and the mixture was stirred 16 hr at 25° C. Toluene wasadded. The mixture was concentrated and more toluene added. This waswashed with K₂CO₃, dried (Na₂SO₄), filtered, and concentrated in vacuo.The residue was crystallized from ether to get the title compound (44mg, m.p. 134-135° C.). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.58 (d, J=8 Hz,1H), 7.19 (dd, J=2, 8 Hz, 1H), 7.10 (dd, J=5, 8 Hz, 1H), 6.95 (m, 1H),4.10 (d, J=8 Hz, 1H), 2.42 (s, 3H), 2.17-2.30 (m, 3H), 2.01 (d, J=13 Hz,2H), 1.82-2.05 (m, 6H), 1.55 (d, J=13 Hz, 2H), 1.54 (s, 6H). MS (ESI+)m/z 428, 430 (M+H)⁺.

Example 54N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-2-methylpropanamideExample 54A 1-Bromoadaman-4-one

5-Hydroxy-2-adamantanone (5.00 g, 30.1 mmol) was mixed with 48%hydrobromic acid (50 mL) and heated at 100° C. for 48 hours (H. W.Geluk, J. L. M. A. Schlatmann, Tetrahedron 24: 5369-5377, 1968).Reaction diluted with water and extracted twice with ether. Combinedextracts dried (Na₂SO₄), decanted, and evaporated under reducedpressure. The residue was purified on normal phase HPLC (silica gel,5-10% ethyl acetate in hexane) to provide the title compound (4.19 g,61%).

Example 54B 1-Bromoadamantan-4-one ethylene ketal

The product of Example 54A (4.19 g, 18.3 mmol), ethylene glycol (2.05mL, 36.6 mmol), and a catalytic amount of p-toluenesulfonic acid (20 mg)were dissolved in benzene (100 mL) and heated at reflux with aDean-Stark apparatus attached for 16 hours (M. Xie, W. J. le Noble, J.Org. Chem. 54: 3836-3839, 1989). The reaction was cooled, washed with 2Nsodium carbonate, water, and brine. The organic solution was dried(Na₂SO₄), filtered, and evaporated under reduced pressure to provide thetitle compound.

Example 54C (1R,2S)-1-Amino-2-indanol-N-4-toluene sulfonamide

(1R,2S)-Aminoindanol (5.00 g, 33.5 mmol) and ethyl acetate (75 mL) wereadded to a solution of sodium carbonate (6.89 g, 65.0 mmol) in water (30mL) that had been stirring at room temperature for 20 minutes. Afterstirring this mixture for 20 minutes, a solution of p-toluenesulfonylchloride (6.20 g, 32.5 mmol) in 1:1 THF/ethyl acetate (12 mL) was addeddrop-wise using an addition funnel over a period of 20 minutes (Z. Han,D. Krishnamurthy, P. Grover, Q. K. Fang, C. H. Senanayake, J. Am. Chem.Soc. 124: 7880-7881, 2002). Reaction stirred 16 hours at roomtemperature. Stirring was stopped, and the layers separated. The organicphase was washed with water, 1N hydrochloric acid, and brine. Theorganic solution was dried (Na₂SO₄), filtered, and evaporated underreduced pressure to provide the title compound.

Example 54D(2R,4R,5S)-3-(4-Toluenesulfonyl)-3.3a,8.8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene-2-oxideand(2S,4R,5S)-3-(4-Toluenesulfonyl)-3.3a,8.8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene-2-oxide

A solution of the product of Example 54C (10.2 g, 33.5 mmol) at −45° C.in anhydrous THF (50 mL) was treated slowly, in one portion, withthionyl chloride (3.67 mL, 50.3 mmol). A solution of imidazole (6.84 g,101 mmol) in anhydrous THF (50 mL) was then added drop-wise to thissolution over 40 minutes using an addition funnel (Z. Han, D.Krishnamurthy, P. Grover, Q. K. Fang, C. H. Senanayake, J. Am. Chem.Soc. 124: 7880-7881, 2002). Reaction stirred two hours at −45° C. andwas then quenched at −45° C. with saturated sodium bicarbonate. Themixture was then diluted with ethyl acetate and warmed to roomtemperature with stirring. The layers were allowed to separate and theorganic phase was washed with water and brine. The organic solution wasdried (Na₂SO₄), filtered, and evaporated under reduced pressure toprovide the title compounds.

Example 54E (S)-(4-Adamantanone ethylene ketal)-1-sulfinicacid-(1R,2S)-1-(4-toluenesulfonylamino)-indan-2-yl ester and(R)-(4-Adamantanone ethylene ketal)-1-sulfinicacid-(1R,2S)-1-(4-toluenesulfonylamino)-indan-2-yl ester

A 0.76M solution of Rieke Zinc (57 mL, 43.0 mmol) in THF was added atroom temperature to a degassed solution under nitrogen containing theproduct of Example 54B (7.82 g, 28.6 mmol) in anhydrous THF (10 mL).Reaction stirred 16 hours at room temperature. More 0.76M Rieke Zinc (50mL, 38.0 mmol) in THF was added, and reaction mixture stirred anadditional 20 hours. This reaction mixture containing the zinc bromidewas added drop-wise using a cannule to a −45° C. solution under nitrogenof the product of Example 54D (6.66 g, 19.1 mmol) in anhydrous THF (10mL). Reaction stirred 16 hours at room temperature. Reaction mixturediluted with ethyl acetate, washed with brine, dried (Na₂SO₄), filtered,and evaporated under reduced pressure. The residue was purified onnormal phase HPLC (silica gel, 30-40% ethyl acetate in hexane) toprovide the title compound.

Example 54F 1-((S)-Aminosulfinyl)adamantan-4-one ethylene ketal and1-((R)-Aminosulfinyl)adamantan-4-one ethylene ketal

A three-necked flask under argon equipped with a glass stir bar, athermometer, a gas inlet, and an ammonia condenser (−78° C.) in a −50°C. bath was charged with anhydrous liquid ammonia (40 mL). A fewcrystals of iron nitrate nonahydrate (5 mg) were added to the ammonia,followed by portion-wise addition of lithium wire (650 mg, 93.7 mmol) ina controlled manner keeping the internal temperature at about −45° C.When all the lithium was added and the blue solution became a greysuspension, the mixture was stirred for an additional two hours at −45°C. The mixture was then cooled to −78° C., and a solution of the productof Example 54E (7.00 g, 12.9 mmol) in anhydrous THF (30 mL) was addeddrop-wise over a period of 30 minutes. Reaction mixture stirred 2 hoursat −78° C. and then quenched with saturated ammonium chloride. Reactionmixture allowed to warm to room temperature, and product extracted withethyl acetate. Extracts washed with brine, dried (Na₂SO₄), filtered, andevaporated under reduced pressure. The residue was purified on normalphase HPLC (silica gel, 5% methanol in ethyl acetate) to provide thetitle compound (1.19 g, 36%).

Example 54G 1-Aminosulfonyladamantan-4-one ethylene ketal

A solution of the product of Example 54F (1.19 g, 4.63 mmol) inanhydrous THF (10 mL) at room temperature was treated with a 2.5 wt. %solution of osmium tetroxide (0.35 mL) in 2-propanol and4-methylmorpholine N-oxide (0.55 g, 4.67 mmol). Reaction stirred at roomtemperature for 16 hours. Reaction diluted with ethyl acetate, washedwith water and brine, dried (Na₂SO₄), filtered, and evaporated underreduced pressure to provide the title compound.

Example 54H 1-Aminosulfonyladamantan-4-one

A solution of the product of Example 54G (1.26 g, 4.63 mmol) in THF (15mL) at room temperature was treated with 1N hydrochloric acid (14 mL).Reaction heated at 60° C. for 16 hours. Reaction quenched with saturatedsodium bicarbonate, and product extracted with 20% methanol inchloroform (2×) and 40% THF in DCM (2×). Extracts dried (Na₂SO₄),filtered, and evaporated under reduced pressure to provide the titlecompound (0.880 g, 82%).

Example 54I E-4-Amino-adamantane-1-sulfonic acid amide

The title compound was prepared according to the procedure outlined inExample 7A substituting the product of Example 54H for4-oxo-adamantane-1-carboxylic acid.

Example 54JN-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-2-methylpropanamide

The product of Example 54I (100 mg, 0.44 mmol),2-(4-chlorophenoxy)-2-methylpropionic acid (93 mg, 0.44 mmol), and TBTU(209 mg, 0.65 mmol) were mixed in DMF (2 mL) at room temperature for 10minutes. N,N-diisopropylethylamine (0.15 mL, 0.87 mmol) was added tothis solution, and the reaction stirred 16 hours at room temperature.Reaction was diluted with ethyl acetate, washed with water, saturatedsodium bicarbonate, IN phosphoric acid, and brine. Organic phase dried(Na₂SO₄), filtered, and evaporated under reduced pressure. The residuewas purified by flash chromatography on silica gel (20-30% ethyl acetatein hexane) to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δppm 7.43 (d, J=6 hz, 1H) 7.33 (d, J=8 Hz, 2H) 6.91 (d, J=8 Hz, 2H) 6.58(s, 2H) 3.79 (m, 1H) 2.04 (bs, 2H) 2.00-1.80 (m, 7H) 1.71 (m, 2H) 1.46(s, 6H) 1.35 (m, 2H). MS (ESI+) m/z 427 (M+H)⁺.

Example 55E-4-({[1-(4-Chlorophenoxy)cyclobutyl]carbonyl}amino)adamantane-1-carboxamideExample 55A Ethyl 1-(4-chlorophenoxy)cyclobutanecarboxylic acid

A mixture of p-chlorophenol (621 mg, 4.83 mmol), ethyl1-bromocyclobutanecarboxylate (1.0 g, 4.83 mmol) and potassium carbonate(1.33 g, 9.66 mmol) in DMF (14.5 ml) was stirred and heated to about55-60° C. under a nitrogen atmosphere for about 18 hours. The solventwas removed under high vacuum, the residue was taken up in diethyl ether(50 ml) and was washed with water and brine (15 ml each). The organiclayer was dried (MgSO₄), and filtered. The solvent was removed undervacuum and the residue was purified by flash column chromatography onsilica gel using hexanes/ethyl acetate (2:1) as the mobile phase toprovide 320 mg (26%) of the title compound. MS (DCI): m/z 272 (M+NH₄)⁺.

Example 55B 1-(4-Chlorophenoxy)cyclobutanecarboxylic acid

To the product of Example 55A (320 mg, 1.26 mmol) was added glacialacetic acid (10 ml) followed by 5% aqueous hydrochloric acid (2.5 ml)and the mixture was heated to reflux for about 18 hours. The mixture wascooled and was evaporated to dryness. The residue was taken up intoluene and was evaporated to dryness two times to provide 250 mg (87%)of the title compound. MS (DCI): m/z 244 (M+NH₄)⁺.

Example 55CE-4-({[1-(4-Chlorophenoxy)cyclobutyl]carbonyl}amino)adamantane-1-carboxylicacid methyl ester

A mixture of the product of Example 55B (207 mg, 0.81 mmol), the productof Example 7B (200 mg, 0.81 mmol),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (523mg, 1.63 mmol) and N,N-diisopropylethylamine (0.57 ml, 3.26 mmol) in DMF(11 ml) was stirred at ambient temperature under a nitrogen atmospherefor about 18 hours. The solvent was evaporated in high vacuum and theresidue was purified by flash column chromatography on silica gel usinghexanes/ethyl acetate (2:1) as the mobile phase to provide 240 mg (70%)of the title compound. MS (DCI) m/z 418 (M+H)⁺.

Example 55DE-4-({[1-(4-Chlorophenoxy)cyclobutyl]carbonyl}amino)adamantane-1-carboxylicacid

To a solution of the product of Example 55C (240 mg, 0.57 mmol) indioxane (8 ml) was added 2N aqueous hydrochloric acid (8 ml) and themixture was heated to about 60° C. for about 18 hours. The mixture wascooled and concentrated in vacuo down to the water phase. Theprecipitate was filtered off and was dried under high vacuum to provide200 mg (86%) of the title compound. MS (DCI) m/z 404 (M+H)⁺.

Example 55EE-4-({[1-(4-Chlorophenoxy)cyclobutyl]carbonyl}amino)adamantane-1-carboxamide

A solution of the product of Example 55D (200 mg, 0.5 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (380 mg,2.0 mmol) and 1-hydroxybenzotriazole hydrate (217 mg, 1.61 mmol) indichloromethane (17 ml) was stirred at ambient temperature under anitrogen atmosphere for about 1 hour. A 0.5 M solution of ammonia indioxane (9.9 ml, 4.95 mmol) was added and stirring was continued forabout 2 hours. Ammonium hydroxide (8.5 ml) was added to the reactionmixture and stirring was continued for about 2 hours. The mixture wasdiluted with dichloromethane (55 ml), the layers were separated, theorganic layer was dried (MgSO₄), filtered, and was evaporated in vacuo.The residue was purified by flash column chromatography on silica gelusing dichloromethane/methanol (15:1) as the mobile phase to provide 113mg (57%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.33-7.29 (m, 2H), 7.08-7.07 (m, 1H), 6.92 (bs, 1H), 6.74-6.70 (m, 2H),6.66 (bs, 1H), 3.76-3.74 (m, 1H), 2.68-2.62 (m, 2H), 2.33-2.25 (m, 2H),1.89-1.64 (m, 11H), 1.37-1.34 (m, 2H), 1.22-1.19 (m, 2H). MS (ESI+) m/z403 (M+H)⁺.

Example 564-[({[((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)methyl]sulfonyl}amino)methyl]benzoicacid Step A

To a solution of the product of Example 36B (395 mg, 0.895 mmol) in DCM(8.9 mL) and DMF (1 drop) was added triphosgene (194 mg, 0.653 mmol) andtriethylamine (0.125 mL, 0.895 mmol). The resulting reaction mixture wasstirred at room temperature for 1.5 hours and then one half of thesolution was added dropwise to a solution of methyl4-(aminomethyl)-benzoate hydrochloride (67.6 mg, 0.447 mmol) andtriethylamine (0.16 mL, 1.12 mmol) in DCM (1.0 mL). After stirring atroom temperature overnight, the reaction was quenched with water andextracted with EtOAc. The organic layer was then rinsed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo.

Step B

The product of Step A was dissolved in a mixture of THF, water, andethanol and treated with excess NaOH. After stirring at room temperatureovernight the reaction was concentrated in vacuo. The crude product waspurified by reverse phase preparative HPLC using acetonitrile: 10 mMNH₄OAc on YMC Guardpak column to provide the title compound (25 mg,10%). ¹H NMR (500 MHz, CDCl₃) δ ppm 8.06 (d, J=8.6 Hz, 2H), 7.44 (d,J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.2 Hz, 1H), 6.86 (d,J=8.6 Hz, 2H), 4.92 (m, 1H), 4.37 (d, J=5.5 Hz, 2H), 4.03 (m, 1H), 2.83(s, 2H), 1.50-2.17 (m, 11H), 1.50 (s, 6H). MS (ESI+) m/z 575 (M+H)⁺.

Example 572-(4-Chlorophenoxy)-N-[(E)-5-(1H-imidazol-2-yl)-2-adamantyl]-2-methylpropanamide

The product of Example 33B (0.1 g, 0.266 mmol) and glyoxal (0.11 g, 40wt % in water, 0.8 mmol) was dissolved in ammonia solution (6 mL, 7 N).The reaction vessel was sealed and stirred at room temperature for 1day. The volatiles were evaporated and the residue was purified byreverse phase HPLC using CH₃CN/0.1% TFA in water to provide the titlecompound as an oil. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.48-1.59 (s, 6H)1.60-1.73 (m, 2H) 1.77-1.94 (m, 2H) 2.02-2.12 (m, 3H) 2.12-2.27 (m, 6H)4.01-4.12 (m, 1H) 6.88-7.02 (m, 2H) 7.21-7.35 (m, 2H) 7.44-7.49 (m, 2H)7.49-7.60 (m, 1H). MS (ESI+) m/z 414.1 (M+H)⁺.

Example 58(2E)-3-((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)acrylicacid Example 58A(2E)-3-((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)acrylicacid ethyl ester

To a cold (0° C.) solution of triethyl phosphonoacetate (0.22 ml, 1.1mmol) in DME (1.0 mL) was added NaH (60% in oil, 42 mg, 1.1 mmol) underN₂ flow. The reaction mixture was stirred for 10 minutes and a solutionof the product of Example 33B (375 mg, 1 mmol) in DME (0.2 ml) was addedslowly at 0° C. It was allowed to warm up to room temperature andstirred for 5 hours. It was quenched with water and extracted with DCM 3times. The combined organic layer was dried over Na₂SO₄, filtered,concentrated under reduced pressure and purified by flash chromatographywith 30% ethyl acetate/70% hexane to provide the title compound, 350 mg(79%). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.20-7.26 (m, 2H), 6.94-7.03 (m,1H), 6.84-6.91 (m, 2H), 6.80 (d, 1H), 5.69 (d, 1H), 4.19 (q, 2H),3.98-4.08 (m, 1H), 1.91-2.08 (m, 3H), 1.46-1.83 (m, 16H), 1.29 (t, 3H).%). MS (ESI+) m/z 446 (M+H)⁺.

Example 58B(2E)-3-((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)acrylicacid

To a solution of the product of Example 58A (45 mg, 0.1 mmol) inTHF/water (0.1 ml/0.05 ml) was added LiOH.H₂O (26 mg, 0.6 mmol). It wasstirred at room temperature overnight. It was acidified with 1N HCl andextracted with DCM 3 times. The combined organic layer was dried overNa₂SO₄, filtered, concentrated under reduced pressure and purified byflash chromatography with 30% ethyl acetate/70% hexane to provide thetitle compound 35 mg (83%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.20-7.28 (m,2H), 6.96-7.04 (m, 1H), 6.82-6.95 (m, 3H), 5.70 (d, 1H), 4.00-4.09 (m,1H), 1.93-2.08 (m, 3H), 1.47-1.85 (m, 16H). MS (ESI+) m/z 418 (M+H)⁺.

Example 59(E)-4-[(2-Methyl-2-{[5-(1H-pyrazol-1-yl)pyridin-2-yl]oxy}propanoyl)amino]adamantane-1-carboxamide

CuI (10.5 mg, 0.055 mmol), N,N,-dimethylglycine (11.3 mg, 0.109 mmol),K₂CO₃ (76 mg, 0.549 mmol), pyrazole (22 mg, 0.329 mmol), and the productof step C of Example 30B (80 mg, 0.183 mmol) was dissolved in DMSO (1mL) and the resulting mixture was heated in Personal Chemistry's EmryOptimizer microwave instrument at 160° C. for 20 minutes. The mixturewas diluted with EtOAc and filtered through a pad of silica and afterevaporation the residue was purified by reverse phase HPLC usingCH₃CN/0.1% TFA in water to give the title compound. ¹H NMR (300 MHz,CD₃OD) δ ppm 1.40-1.64 (m, 4H) 1.66-1.76 (m, 7H) 1.77-1.87 (m, 3H)1.90-2.04 (m, 7H) 3.93 (s, 1H) 6.53 (dd, J=2.54, 1.86 Hz, 1H) 7.01 (d,J=8.82 Hz, 1H) 7.72 (d, J=2.03 Hz, 1H) 8.07 (dd, J=8.99, 2.88 Hz, 1H)8.15 (d, J=3.05 Hz, 1H) 8.45 (d, J=2.71 Hz, 1H) 8.45 (d, J=2.71 Hz, 1H).MS (ESI+) m/z 424.2 (M+H)⁺.

Example 602-(4-Chlorophenoxy)-N-[(E)-5-isoxazol-5-yl-2-adamantyl]-2-methylpropanamideExample 60A2-(4-Chlorophenoxy)-2-methyl-N-[(E)-5-propynoyl-adamantan-2-yl]-propionamideStep A

Acetylenemagnesium chloride (8.22 mL, 0.5 M in THF, 4.11 mmol) was addeddropwise to a stirred and cooled (−78° C.) solution of the product ofExample 33B (0.514 g, 1.37 mmol) in dry THF. The resulting solution waswarmed gradually to room temperature before it was quenched withsaturated NH₄Cl solution. The mixture was partitioned with Et₂O andwater. The organic phase was washed with brine, dried (MgSO₄), filtered,and evaporated to give crude alcohol as an oil.

Step B

Dess-Matin periodinane (1 g, 2.43 mmol) was added in one portion to asolution of the product of Step A (0.65 g, 1.62 mmol) in dry CH₂Cl₂. Theresulting solution was stirred for 3 hours at room temperature before itwas quenched with saturated NaHCO₃ solution and Na₂S₂O₃ solution. Themixture was stirred for 1 hour before the phases were separated. Theorganic phase was dried (Na₂SO₄), filtered, and the solvent wasevaporated. The residue was purified over silica gel using 30% EtOAc inhaxanes to provide the title compound as a yellow solid.

Example 60B2-(4-Chlorophenoxy)-N-[(E)-5-isoxazol-5-yl-2-adamantyl]-2-methylpropanamide

NH₂OH.HCl (0.23 g, 2.75 mmol) and K₂CO₃ (0.38 g, 2.75 mmol) was added toa solution of the product of Step B of Example 60A (0.11 g, 0.275 mmol)in isopropanol. The reaction was heated (80° C.) for 3 hours. Thereaction mixture was diluted with EtOAc and filtered through a pad ofCelite and after evaporation the residue was purified by reverse phaseHPLC using CH₃CN/0.1% TFA in water to provide the title compound. ¹H NMR(300 MHz, CD₃OD) δ ppm 1.53 (s, 6H) 1.65 (d, 2H) 1.91-2.04 (m, 4H) 2.11(s, 6H) 4.06 (d, J=7.46 Hz, 1H) 6.12 (d, J=2.03 Hz, 1H) 6.96 (d, J=8.82Hz, 2H) 7.29 (d, J=9.16 Hz, 2H) 7.48 (d, J=6.78 Hz, 1H) 8.25 (d, J=2.03Hz, 1H). MS (ESI+) m/z 415.1 (M+H)⁺.

Example 612-(4-Chlorophenoxy)-2-methyl-N-{(E)-5-[(2-morpholin-4-ylethoxy)methyl]-2-adamantyl}propanamide

A solution of the product of Example 33A (61 mg, 0.16 mmol) and4-(2-Chloro-ethyl)-morpholine hydrochloride (36 mg, 0.19 mmol) in DMF (4mL) was treated with sodium hydride (60%, 20.0 mg, 0.5 mmol) and wasstirred at 100° C. for 24 hours. Then the reaction mixture was cooledand filtered. The filtrate was concentrated under reduced pressure toprovide crude title compound that was purified by reverse phasepreparative HPLC using acetonitrile: 10 mM NH₄OAc on YMC Guardpak columnto afford the title compound. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.41 (s, 1H)7.26-7.30 (m, 2H) 6.93-6.96 (m, 2H) 3.92 (s, 1H) 3.66-3.72 (m, 4H) 3.56(t, J=5.49 Hz, 2H) 3.03 (s, 2H) 2.59 (t, J=5.49 Hz, 2H) 2.52-2.57 (m,4H) 1.96 (d, J=2.14 Hz, 2H) 1.86 (s, 1H) 1.72 (s, 1H) 1.69 (s, 1H) 1.67(s, 4H) 1.57 (d, J=3.36 Hz, 2H) 1.53 (s, 2H) 1.51 (s, 6H). MS (ESI+) m/z491 (M+H)⁺.

Example 62N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chlorophenoxy)-2-methylpropanamideExample 62A 2-(2-Chlorophenoxy)-2-methylpropionic acid

The title compound was prepared according to the procedure outlined inExample 44C substituting 2-chlorophenol for the product of Example 44B.

Example 62BN-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chlorophenoxy)-2-methylpropanamide

The title compound was prepared according to the procedure outlined inExample 54J substituting the product of Example 62A for2-(4-chlorophenoxy)-2-methylpropionic acid. ¹H NMR (400 MHz, CDCl₃) 5ppm 7.61 (d, J=8 Hz, 1H), 7.42 (dd, J=8 & 2 Hz, 1H), 7.21 (m, 1H), 7.13(dd, J=8 & 2 Hz, 1H), 7.05 (m, 1H), 4.32 (s, 2H), 4.09 (m, 1H),2.30-2.10 (m, 8H), 1.90 (m, 2H), 1.60 (m, 3H), 1.46 (s, 6H). MS (ESI+)m/z 427 (M+H)⁺.

Example 63N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-(2-methylphenoxy)propanamideExample 63A 2-Methyl-2-(2-methylphenoxy)propionic acid

The title compound was prepared according to the procedure outlined inExample 44C, substituting 2-methylphenol for the product of Example 44B.

Example 63BN-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-(2-methylphenoxy)propanamide

The title compound was prepared according to the procedure outlined inExample 54J substituting the product of Example 63A for2-(4-chlorophenoxy)-2-methylpropionic acid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.19 (dd, J=8 & 2 Hz, 1H), 7.14 (d, J=8Hz, 1H), 7.09 (m, 1H), 6.96 (m, 1H), 6.86 (dd, J=8 & 2 Hz, 1H), 4.33 (s,2H), 4.09 (m, 1H), 2.28 (s, 3H), 2.30-2.05 (m, 8H), 1.71 (m, 2H), 1.59(m, 3H), 1.52 (s, 6H). MS (ESI+) m/z 407 (M+H)⁺.

Example 64N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-(4-methylphenoxy)propanamideExample 64A 2-Methyl-2-(4-methylphenoxy)propionic acid

The title compound was prepared according to the procedure outlined inExample 44C, substituting 4-methylphenol for the product of Example 44B.

Example 64BN-[(E)-5-(Aminosulfonyl-2-adamantyl]-2-methyl-2-(4-methylphenoxy)propanamide

The title compound was prepared according to the procedure outlined inExample 54J substituting the product of Example 64A for2-(4-chlorophenoxy)-2-methylpropionic acid.

¹H NMR (400 MHz, CDCl₃) 5 ppm 7.14 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz,2H), 6.82 (d, J=8 Hz, 1H), 4.46 (s, 2H), 4.06 (m, 1H), 2.31 (s, 3H),2.30-2.00 (m, 8H), 1.72 (m, 2H), 1.59 (m, 3H), 1.49 (s, 6H). MS (ESI+)m/z 407 (M+H)⁺.

Example 65N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethyl)phenoxy]propanamideExample 65A 2-Methyl-2-(2-trifluoromethylphenoxy)propionic acid

The title compound was prepared according to the procedure outlined inExample 44C, substituting 2-trifluoromethylphenol for the product ofExample 44B.

Example 65BN-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethyl)phenoxy]propanamide

The title compound was prepared according to the procedure outlined inExample 54J substituting the product of Example 65A for2-(4-chlorophenoxy)-2-methylpropionic acid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.61 (dd, J=8 & 2 Hz, 1H), 7.45 (m, 1H),7.11 (m, 2H), 7.01 (d, J=8 Hz, 1H), 4.42 (s, 2H), 4.06 (m, 1H),2.30-2.05 (m, 8H), 1.70 (m, 3H), 1.64 (s, 6H), 1.55 (m, 2H). MS (ESI+)m/z 461 (M+H)⁺.

Example 66N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethoxy)phenoxy]propanamideExample 66A 2-Methyl-2-(2-trifluoromethoxyphenoxy)propionic acid

The title compound was prepared according to the procedure outlined inExample 44C, substituting 2-trifluoromethoxylphenol for the product ofExample 44B.

Example 66BN-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethoxy)phenoxy]propanamide

The title compound was prepared according to the procedure outlined inExample 54J substituting the product of Example 66A for2-(4-chlorophenoxy)-2-methylpropionic acid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.31 (dd, J=8 & 2 Hz, 1H), 7.22 (m, 1H),7.18 (d, J=8 Hz, 1H), 7.08 (m, 2H), 4.39 (s, 2H), 4.05 (m, 1H),2.30-2.05 (m, 8H), 1.75 (m, 2H), 1.59 (m, 3H), 1.55 (s, 6H). MS (ESI+)m/z 427 (M+H)⁺.

Example 67N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chloro-4-fluorophenoxy)-2-methylpropanamide

The title compound was prepared according to the procedure outlined inExample 54J substituting the product of Example 49A for2-(4-chlorophenoxy)-2-methylpropionic acid. ¹H NMR (400 MHz, CDCl₃) δppm 7.54 (d, J=8 Hz, 1H), 7.17 (m, 1H), 7.08 (m, 1H), 6.93 (m, 1H), 4.26(s, 2H), 4.08 (m, 1H), 2.35-2.05 (m, 8H), 1.87 (m, 2H), 1.60 (m, 3H),1.54 (s, 6H). MS (ESI+) m/z 445 (M+H)⁺.

Biological Data Measurement of Inhibition Constants:

The ability of test compounds to inhibit human 11β-HSD-1 enzymaticactivity in vitro was evaluated in a Scintillation Proximity Assay(SPA). Tritiated-cortisone substrate, NADPH cofactor and titratedcompound were incubated with truncated human 11β-HSD-1 enzyme (24-287AA)at room temperature to allow the conversion to cortisol to occur. Thereaction was stopped by adding a non-specific 11β-HSD inhibitor,18β-glycyrrhetinic acid. The tritiated cortisol was captured by amixture of an anti-cortisol monoclonal antibody and SPA beads coatedwith anti-mouse antibodies. The reaction plate was shaken at roomtemperature and the radioactivity bound to SPA beads was then measuredon a p-scintillation counter. The 11-βHSD-1 assay was carried out in96-well microtiter plates in a total volume of 220 μl. To start theassay, 188 μl of master mix which contained 17.5 nM ³H-cortisone, 157.5nM cortisone and 181 mM NADPH was added to the wells. In order to drivethe reaction in the forward direction, 1 mM G-6-P was also added. Solidcompound was dissolved in DMSO to make a 10 mM stock followed by asubsequent 10-fold dilution with 3% DMSO in Tris/EDTA buffer (pH 7.4).22 μl of titrated compounds was then added in triplicate to thesubstrate. Reactions were initiated by the addition of 10 μl of 0.1mg/ml E. coli lysates overexpressing 11β-HSD-1 enzyme. After shaking andincubating plates for 30 minutes at room temperature, reactions werestopped by adding 101 of 1 mM glycyrrhetinic acid. The product,tritiated cortisol, was captured by adding 10 μl of 1 μM monoclonalanti-cortisol antibodies and 100 μl SPA beads coated with anti-mouseantibodies. After shaking for 30 minutes, plates were read on a liquidscintillation counter Topcount. Percent inhibition was calculated basedon the background and the maximal signal. Wells that contained substratewithout compound or enzyme were used as the background, while the wellsthat contained substrate and enzyme without any compound were consideredas maximal signal. Percent of inhibition of each compound was calculatedrelative to the maximal signal and IC₅₀ curves were generated. Thisassay was applied to 11β-HSD-2 as well, whereby tritiated cortisol andNAD⁺ were used as substrate and cofactor, respectively.

Compounds of the present invention are active in the 11-βHSD-1 assaydescribed above and show selectivity for human 11-β-HSD-1 over human11-β-HSD-2, as indicated in Table 1.

TABLE 1 11-β-HSD-1 and 11-β-HSD-2 activity for representative compounds.Compound 11-β-HSD-1 IC₅₀ (nM) 11-β-HSD-2 IC₅₀ (nM) A (Example 2)28 >10,000 B (Example 3) 35 10,000 C (Example 5) 35 D (Example 6) 34 E(Example 7) 72 29,000 F (Example 15) 24 32,000 G (Example 16) 44 11,000H (Example 22) 40 2,600 I (Example 24) 38 15,000 J (Example 26) 4537,000 K (Example 32) 18 35,000 L (Example 33) 45 59,000 M (Example 34)43 21,000 N (Example 35) 41 >100,000 O (Example 36) 96 100,000 P(Example 37) 41 >100,000 Q (Example 41) 29 10,000 R (Example 47) 6865,000 S (Example 52) 53 10,000 T (Example 53) 28 10,000 U (Example 54)26 14,000 V (Example 55) 89 90,000 W (Example 56) 48 18,000 X (Example58) 30 >100,000 Y (Example 59) 30 >100,000 Z (Example 67) 89 >100,000

The data in Table 1 demonstrates that compounds A-Z are active in thehuman 11β-HSD-1 enzymatic SPA assay described above and that the testedcompound showed selectivity for 11β-HSD-1 over 11β-HSD-2. The 11β-HSD-1inhibitors of this invention generally have an inhibition constant IC₅₀of less than 600 nM and preferably less than 50 nM. The compoundspreferably are selective, having an inhibition constant IC₅₀ against11β-HSD-2 greater than 1000 nM and preferably greater than 10,000 nM.Generally, the IC₅₀ ratio for 11β-HSD-2 to 11β-HSD-1 of a compound is atleast 10 or greater and preferably 100 or greater.

Metabolic Stability Incubation Conditions:

Metabolic stability screen: each substrate (10 μM) was incubated withmicrosomal protein (0.1-0.5 mg/ml) in 50 mM potassium phosphate buffer(pH 7.4) in 48-Well plate. The enzyme reaction was initiated by theaddition of 1 mM NADPH, then incubated at 37° C. in a Form a Scientificincubator (Marietta, Ohio, USA) with gentle shaking. The reactions werequenched by the addition of 800 μl of ACN/MeOH (1:1, v/v), containing0.5 μM of internal standard (IS), after 30 min incubation. Samples werethen filtered by using Captiva 96-Well Filtration (Varian, Lake Forest,Calif., USA) and analyzed by LC/MS (mass spectrometry). Liver microsomalincubations were conducted in duplicate.

LC/MS Analysis:

The parent remaining in the incubation mixture was determined by LC/MS.The LC/MS system consisted of an Agilent 1100 series (AgilentTechnologies, Waldbronn, Germany) and API 2000 (MDS SCIEX, Ontario,Canada). A Luna C8(2) (50×2.0 mm, particle size 3 μm, Phenomenex,Torrance, Calif., USA) was used to quantify each compound at ambienttemperature. The mobile phase consisted of (A): 10 mM NH₄AC (pH 3.3) and(B): 100% ACN and was delivered at a flow rate of 0.2 ml/min. Elutionwas achieved using a linear gradient of 0-100% B over 3 min, then held100% B for 4 min and returned to 100% A in 1 min. The column wasequilibrated for 7 min before the next injection.

The peak area ratios (each substrate over IS) at each incubation timewere expressed as the percentage of the ratios (each substrate over IS)of the control samples (0 min incubation). The parent remaining in theincubation mixture was expressed as the percentage of the values at 0min incubation. The percentage turnover is calculated using thefollowing equation (% turnover=100% turnover−% parent remaining) and isrecorded as the percentage turnover in the Table 2.

TABLE 2 Microsomal metabolic stability. Human Liver Mouse LiverMicrosomal Microsomal Compound Turnover (%) Turnover (%) A 19 37 B 47 25E 0 0 EE (Example 18) 88 86

Compounds A, B and E contain a substituted adamantane, whereas theadamantane ring of compound EE is unsubstituted. The microsomal,metabolic, stability data in Table 2 demonstrates that substitutedadamantane compounds of the present invention may exhibit an increase inmetabolic stability compared to unsubstituted adamantane compounds whichmay lead to longer in vivo half lives and pharmacokinetic advantagesover unsubstituted adamantanes.

Selective 11β-HSD1 Inhibitors Enhance Memory Consolidation in Mice after2-Week Food-in-Diet Dosing

Episodic memory is a type of long-term memory that requires one exposurefor memory formation to occur. Patients with Alzheimer's disease sufferfrom episodic memory dysfunction, among other cognitive deficits. Inaddition, studies indicate that patients with a genetic risk forAlzheimer's disease have early deficits in episodic memory and executivefunction (Ringman, J. Geriatr. Psychiatry Neurology, 2005, 18:228-233).

The 24-hour inhibitory avoidance task in mice is a measure of one-triallearning and memory consolidation in response to a discrete aversiveevent (foot-shock). Mice are first placed in an illuminated compartmentof a two-compartment apparatus. Mice will naturally step through into anadjoining dark compartment, which they prefer. When the mice enter thedark they receive a mild foot-shock. To assess memory, mice are tested24 hours later and the length of time the animal refrains from enteringthe dark compartment is recorded (higher latencies indicate improvedmemory for the aversive event).

Male CD-1 mice were obtained from Charles River, Wilmington, Mass. Micewere group-housed 10 per cage. The body weight upon arrival was 20-25 g.Food and water were available ad libitum except during experiments.Animals were acclimated to the animal facilities for a period of atleast one week prior to commencement of experiments. Animals were testedin the light phase of a 12-hour light: 12-hour dark schedule (lights on0600 hours).

Compound AA([2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylsulfonyl)-2-adamantyl]propanamide])was synthesized at Abbott Laboratories. Compound AA was administered viaa drug-in-diet administration (100 mg/kg/day in Western diet) or (10mg/kg/day in Western diet).

On the first day of testing (17 days after drug-in-diet was presented)mice were removed from the colony room in their home cage, brought tothe testing room, and left undisturbed for 2 hours prior to testinginitiation. Following this habituation period, drug-in-diet mice weretested. Upon testing initiation, mice were placed one at a time into thelight (safe) compartment of a two-chambered apparatus (Gemini apparatus,San Diego Instruments, San Diego, Calif.), during which time theretractable door was closed. After 30 sec at the completion of theacclimation period the door between the light and dark compartments wasopened. Measurement of the training latency commenced at this point.This measure (training) provides some indication of general locomotoractivity. If a mouse has not crossed within 60 s the animal's data isexcluded from the analysis. After the mouse crossed into the darkchamber the door was lowered and inescapable footshock (0.13 mA, 1 secduration) was presented to the mouse after it completely entered thechamber and the door closed. The mouse was immediately removed from thechamber and returned to the home cage. 24-hours later the mouse wastested using methods identical to those on the training day, exceptwithout being dosed and without shock presentation. The latency to enterthe dark chamber was recorded and was the dependent variable measuredfor assessing memory retention (latency is defined as entry of the wholemouse; all 4 paws on the grids in the dark side, plus the tail in thechamber for 5 sec; 180 sec is maximum latency). Data were analyzed usingMann Whitney U comparisons. P<0.05 was regarded as significant. Asillustrated in FIG. 1, there was a significant improvement in memoryretention following the administration of Compound AA at both dosescompared to the response of vehicle control mice.

A Selective 11β-HSD1 Inhibitor Enhances Phosphorylated CREB. ABiochemical Marker of Cognitive Enhancement, in Mice after 2-WeekFood-in-Diet Dosing

In vivo signaling studies were conducted to examine the biochemicalpathways that may be mechanistically involved in the cognitive efficacyassociated with Compound AA. An important signaling process that servesas a biochemical correlate of synaptic plasticity underlying learningand memory is the phosphorylation of CREB (c-AMP-response elementbinding protein), a transcription factor critical to long-term memory.To investigate the effects of Compound AA on CREB phosphorylation, CD1mice treated and tested (data presented in FIG. 1) were given a 24-hourrest after testing before immunohistochemical procedures commenced.

Male CD-1 mice were obtained from Charles River, Wilmington, Mass. Micewere group-housed 10 per cage. The body weight upon arrival was 20-25 g.Food and water were available ad libitum except during experiments.Animals were acclimated to the animal facilities for a period of atleast one week prior to commencement of experiments. Animals were testedin the light phase of a 12-hour light: 12-hour dark schedule (lights on0600 hours).

Compound AA was administered via a drug-in-diet administration (100mg/kg/day in Western diet) or (10 mg/kg/day in Western diet). 18-daysafter receiving Compound AA food-in-diet (10 and 100 mg/kg/day) ratswere anesthetized and perfused through the aorta with normal salinefollowed by 10% formalin. Following perfusion, brains were removed andpostfixed in 20% sucrose-PBS (phosphate buffered saline) overnight andsubsequently cut on a cryostat (40 μm coronal sections) and collected asfree-floating sections in PBS. Sections were then immunostained for Fosprotein using a 3-step ABC-peroxidase technique beginning with a 30-minincubation with blocking serum. Sections were next incubated withanti-phospho-CREB (rabbit IgG, 1:1000, Cell signaling) antibodies for 48hrs at 4 degrees C., washed with PBS and incubated for 1-hr with eitherbiotinylated secondary anti-sheep or anti-mouse antibody (Ab) solution(1:200). Finally, sections were washed in PBS, incubated with ABCreagent (Vector) and then developed in a peroxidase substrate solution.The sections were mounted, coverslipped and examined and photographedwith a light microscope (Leica, DMRB). Immuno-reactivity (IR) wasquantified using an image analysis system (Leica, Quantimet 500) thatdetermined number and/or area of peroxidase substrate-positive stainedneurons from digitized photomicrographs according to a pixel gray levelempirically determined prior to analysis. Overall statisticalsignificance was determined using a one-way ANOVA, with Dunnett's posthoc analyses used to determine significance (p<0.05 was consideredsignificant). FIG. 2 shows the increase in phosphorylated CREB followingthe administration of Compound AA mg/kg/day.

Selective 11β-HSD1 Inhibitors Enhance Memory Consolidation in Mice afterSubchronic Dosing

The 24-hour inhibitory avoidance model in mice was used to evaluate theeffects of Compound AA and Compound BB([N-{(E)-5-[(Z)-Amino(hydroxyimino)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide])following a subchronic (3 administration) dosing regimen.

Male CD-1 mice were obtained from Charles River, Wilmington, Mass. Micewere group-housed 10 per cage. The body weight upon arrival was 20-25 g.Food and water were available ad libitum except during experiments.Animals were acclimated to the animal facilities for a period of atleast one week prior to commencement of experiments. Animals were testedin the light phase of a 12-hour light: 12-hour dark schedule (lights on0600 hours).

Compound AA and Compound BB were synthesized at Abbott Laboratories.Compounds AA and BB were solubilized in a solution of 5% Tween80/water.Compound AA was administered in a cloudy, fine suspension, whileCompound BB was administered in a solution.

Mice were weighed and dosed BID (≈8 AM and 3 PM) PO with Compound AA (30mg/kg), or Compound BB (30 mg/kg) or vehicle the day before training. Ontraining day, mice were injected with Compound AA, Compound BB orvehicle one-hour PO before training. One hour following injection (startof training) mice were subjected to a training session in which theywere placed in a lighted compartment of a two-compartment chamber(Gemini apparatus, San Diego Instruments, San Diego, Calif.) with amanually operated gate separating the compartments. Following a 30second habituation period in the lighted compartment, the door to theadjacent dark compartment was opened. Once the mouse had completelytransferred, the door was closed and a 0.13 mA current was applied tothe grid floor for 1 s. The mouse was then immediately removed andreturned to the home cage. Twenty-four hours later mice were againtested in the same apparatus, except without shock, and the transferlatency from the lighted to the dark compartment recorded and used as anindex of memory for the punished response 24 hours earlier. The electricshock parameters of this test were established such that vehicle treatedmice would only have minimal retention of the conditioning trial, thusallowing a large window for improvement of the memory following drugtreatment. Data were analyzed using Mann Whitney U comparisons. P<0.05was regarded as significant.

As illustrated in FIG. 3, there was a significant improvement in memoryretention following the administration of both Compounds AA and BBcompared to the response of vehicle control mice.

a Selective 11-HSD1 Inhibitor Enhances Short-Term Memory in Rats afterSubchronic Dosing

Social memory and social cognition are impaired in disorders such asAlzheimer's disease and schizophrenia. One of the more commonly usedpreclinical models of social recognition memory is short-term socialrecognition in the rat, a model of short-term memory based on therecognition of a juvenile rat by an adult rat. When adult rats areallowed to interact with a juvenile rat for 5 min, the adult exhibitsbehaviors such as close following, grooming or sniffing the juvenile foras much as 40-50% of the duration of a 5 min trial. The juvenile rat isthen removed and reintroduced 120 min later, and interactive behavior ofthe adult rat is again monitored. If memory has been lost over theinterval between trials 1 and 2, the extent of interaction is equal(expressed as a ratio of investigation time of T1/T2) and the ratio willbe close to 1. However, if the adult remembers the juvenile, theinvestigation ratio declines. To test for non-specific effects, a noveljuvenile is introduced at 120 minutes instead of the familiar juvenile.If the ratio is less than 1, this indicates the drug is having effectsthat may not be specific to cognition.

Male Sprague Dawley rats from Charles Rivers (Portage, Mich., USA) wereused. Adults weighed 370-500 g, and juveniles weighed 70-120 g at thetime of testing. All animals were housed in a quiet room underconditions of 12 h lights on/12 h lights off (on at 06:00 am) in groupsof four with food and water available ad libitum. Studies were conductedbetween 08:00 h and 16:00 h, and treatment groups were arranged forequal representation of time of day. Compound CC([N-[(E)-5-Hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}acetamide],30 mg/kg) was dissolved in PEG 400 using a warm sonicator bath. Compoundwas administered in solution in a volume of 1 mL/1 g body weight, p.o.

Rats were pre-dosed po at 24, 18 and 1 hour before first juvenile ratexposure with vehicle, or Compound CC (30 mg/kg). During testing, theadult rat was placed into the test cage. After 30 min, a juvenile ratwas placed into the test cage with the adult rat for 5 min. The time theadult spent exploring (sniffing, grooming, close following) the juvenileduring this test session was recorded, and defined as the firstinvestigation duration. The juvenile was then removed from the testcage, and placed into its home cage. Following a further 90 min, theadult was placed back into the same test chamber, for a second 30-minhabituation. Following this second habituation the same juvenile(familiar) was again placed into the test cage for a 5-min test session;the time spent exploring the juvenile during this test session wasdefined as the second investigation duration. Vehicle treated rats donot remember the familiar juvenile following this two hr delay. Datawere analyzed using a one-way analysis of variance. If there was asignificant effect, subsequent post hoc significance was determinedusing Dunnett's multiple comparison testing (p<0.05 was regarded assignificant).

As shown in FIG. 4, there was a significant improvement in short-termmemory retention following the administration of Compound CC compared tothe response of vehicle control rats.

Effects of 11βHSD-1 Inhibitor on Rat Wake EEG Power Spektrum and REMSleep Parameter

EEG of Fisher rats (n=8/group) with chronically implanted supracorticalEEG-electrodes were analyzed for an 8 h period. Intraindividualdrug-induced changes of power spectra were analyzed. For REM sleep thenumber of REM episodes, latency to first REM, and total REM time wasanalyzed. Compound CC (30 mg/kg; 3 times at 24, 26, and 0.1 hours beforemeasurement) significantly reduced the number of REM sleep episodes by16% (total sleep time by 10%); the corresponding REM time was reduced by23%. The latency to first REM significantly increased by 62% (See FIGS.5 a, 5 b and 5 c, respectively).

The observed effects on REM were in line with the effects ofantidepressants like SSRIs and TCAs. These effects differ from theprocognitive effects induced by inhibitors of ACh-esteras like donepeziland physostigmine.

Modulation of Cortical/Hippocampal Acetylcholine Serotonin Release by11β-HSD1 Inhibition

Microdialysis studies (resting or challenging conditions) in freelymoving, male Sprague Dawley rats (Janvier, 295-315 g, n=5-8/treatmentgroup) were performed using stereotactically instrumented microdialysisprobes (CMA/12-14-2): mPFC, hippocampus. Aliquots of the samemicrodialysate fractions (6 before, and 9-12 after compoundadministration) were analyzed either for acetylcholine or for serotoninby HPLC and electrochemical detection.

Microdialysate Acetylcholine Levels

Acute, single administration of Compound CC (30 mg/kg, p.o.) did notchange ACh release under resting conditions. Challenging conditions asthe transfer from home cage to novel cage, and back to home cageresulted in stimulation of ACh release (see FIGS. 6 a, 6 b and 6 c).Single administration of Compound CC did not induce any furtherstimulation of ACh release, neither in the cortex nor in thehippocampus.

Microdialysate Serotonin Levels

Single administration of Compound CC (30 mg/kg, p.o.) resulted in along-lasting increase of serotonin (5-HT) levels in the medialprefrontal cortex and in the hippocampus. This is a feature shared bymarketed anti-depressive drugs and might indicate the potential use for11β-HSD1 inhibitors as antidepressants/anxiolytic drugs. These findingsremain to be confirmed by (i) investigating 11β-HSD1 inhibitors fromdifferent chemotype(s) in selected microdialysis studies and/or (ii) inanimal models of depression/anxiety. Additionally, these resultsdifferentiate 11β-HSD-1 inhibition from acetylcholine esteraseinhibition, the current therapeutic principle for symptomatic treatmentof Alzheimer's disease.

Effects of HSD-1 Inhibitors on Monkey Ex Vivo HSD1 Activity

Compound AA demonstrated potent ex vivo inhibition of monkey brain, fatand liver 2.5 and 16 hours following a single oral 10 mg/kg dose.Harvested tissues (approximately 150 mg) were minced into small, 2 mmpieces in the presence of 5× volume of incubation buffer. Cortisone atfinal concentrations of 0, 3, 10 or 30 μM was added to each well. Cellculture plates with tissues were incubated at 37° C. for three hours.Two-hundred μL of tissue culture supernatant was then removed and spunat 1000 rpm in an Eppindorf tube, and then 100 μL of resultingsupernatant was aliquotted into two tubes for LCMS analysis of cortisol.Results are indicated as & vehicle control activity in the table below:

TABLE 3 HSD-1 Ex Vivo Activity in Cynomolgus Monkeys Following a Single10 mg/kg Oral Dose of Compound AA N = 3/group Tissue Time Mean % VehControl Liver 2.5 hours  38% Mesenteric Fat 2.5 hours  90% Liver 16hours  9% Mesenteric Fat 16 hours 50% Cerebral Cortex 16 hours 30%Hippocampus 16 hours 42%

Biochemical Mechanism

Glucocorticoids are steroid hormones that play an important role inregulating multiple physiological processes in a wide range of tissuesand organs. For example, glucocorticoids are potent regulators ofglucose and lipid metabolism. Excess glucocorticoid action may lead toinsulin resistance, type 2 diabetes, dyslipidemia, visceral obesity andhypertension. Cortisol is the major active and cortisone is the majorinactive form of glucocorticoids in humans, while corticosterone anddehydrocorticosterone are the major active and inactive forms inrodents.

Previously, the main determinants of glucocorticoid action were thoughtto be the circulating hormone concentration and the density ofglucocorticoid receptors in the target tissues. In the last decade, itwas discovered that tissue glucocorticoid levels may also be controlledby 11β-hydroxysteroid dehydrogenases enzymes (11β-HSDs). There are two11β-HSD isozymes which have different substrate affinities andcofactors. The 11β-hydroxysteroid dehydrogenases type 1 enzyme(11β-HSD-1) is a low affinity enzyme with K_(m) for cortisone in themicromolar range that prefers NADPH/NADP⁺ (nicotinamide adeninedinucleotide) as cofactors. 11β-HSD-1 is widely expressed andparticularly high expression levels are found in liver, brain, lung,adipose tissue and vascular smooth muscle cells. In vitro studiesindicate that 11β-HSD-1 is capable of acting both as a reductase and adehydrogenase. However, many studies have shown that it is predominantlya reductase in vivo and in intact cells. It converts inactive11-ketoglucocorticoids (i.e., cortisone or dehydrocorticosterone) toactive 11-hydroxyglucocorticoids (i.e., cortisol or corticosterone) andtherefore amplifies the glucocorticoid action in a tissue-specificmanner.

With only 20% homology to 11-HSD-1, the 11β-hydroxysteroiddehydrogenases type 2 enzyme (11β-HSD-2) is a NAD⁺-dependent, highaffinity dehydrogenase with a K_(m) for cortisol in the nanomolar range.11β-HSD-2 is found primarily in mineralocorticoid target tissues, suchas kidney, colon and placenta. Glucocorticoid action is mediated by thebinding of glucocorticoids to receptors, such as mineralocorticoidreceptors and glucocorticoid receptors. Through binding to its receptor,the main mineralocorticoid aldosterone controls the water and saltsbalance in the body. However, the mineralocorticoid receptors have ahigh affinity for both cortisol and aldosterone. 11β-HSD-2 convertscortisol to inactive cortisone, therefore preventing the non-selectivemineralocorticoid receptors from being exposed to high levels ofcortisol. Mutations in the gene encoding 11β-HSD-2 cause ApparentMineralocorticoid Excess Syndrome (AME), which is a congenital syndromeresulting in hypokaleamia and severe hypertension. AME Patients haveelevated cortisol levels in mineralocorticoid target tissues due toreduced 11β-HSD-2 activity. The AME symptoms may also be induced byadministration of 11β-HSD-2 inhibitor, glycyrrhetinic acid. The activityof 11β-HSD-2 in placenta is probably important for protecting the fetusfrom excess exposure to maternal glucocorticoids, which may result inhypertension, glucose intolerance and growth retardation. Due to thepotential side effects resulting from 11β-HSD-2 inhibition, the presentinvention describes selective 11β-HSD-1 inhibitors.

Glucocorticoid levels and/or activity may contribute to numerousdisorders, including Type II diabetes, obesity, dyslipidemia, insulinresistance and hypertension. Administration of the compounds of thepresent invention decreases the level of cortisol and other11β-hydroxysteroids in target tissues, thereby reducing the effects ofglucocorticoid activity in key target tissues. The present inventioncould be used for the treatment, control, amelioration, prevention,delaying the onset of or reducing the risk of developing the diseasesand conditions that are described herein.

Since glucocorticoids are potent regulators of glucose and lipidmetabolism, glucocorticoid action may contribute or lead to insulinresistance, type 2 diabetes, dyslipidemia, visceral obesity andhypertension. For example, cortisol antagonizes the insulin effect inliver resulting in reduced insulin sensitivity and increasedgluconeogenesis. Therefore, patients who already have impaired glucosetolerance have a greater probability of developing type 2 diabetes inthe presence of abnormally high levels of cortisol. Previous studies (B.R. Walker et al., J. of Clin. Endocrinology and Met., 80: 3155-3159,1995) have demonstrated that administration of non-selective 11β-HSD-1inhibitor, carbenoxolone, improves insulin sensitivity in humans.Therefore, administration of a therapeutically effective amount of an11β-HSD-1 inhibitor may treat, control, ameliorate, delay, or preventthe onset of type 2 diabetes.

Administration of glucocorticoids in vivo has been shown to reduceinsulin secretion in rats (B. Billaudel et al., Horm. Metab. Res. 11:555-560, 1979). It has also been reported that conversion ofdehydrocorticosterone to corticosterone by 11β-HSD-1 inhibits insulinsecretion from isolated murine pancreatic β cells. (B. Davani et al., J.Biol. Chem., 275: 34841-34844, 2000), and that incubation of isolatedislets with an 11β-HSD-1 inhibitor improves glucose-stimulated insulinsecretion (H Orstater et al., Diabetes Metab. Res. Rev. 21: 359-366,2005). Therefore, administration of a therapeutically effective amountof an 11β-HSD-1 inhibitor may treat, control, ameliorate, delay, orprevent the onset of type 2 diabetes by improving glucose-stimulatedinsulin secretion in the pancreas.

Abdominal obesity is closely associated with glucose intolerance (C. T.Montaque et al., Diabetes, 49: 883-888, 2000), hyperinsulinemia,hypertriglyceridemia and other factors of metabolic syndrome (also knownas syndrome X), such as high blood pressure, elevated VLDL and reducedHDL. Animal data supporting the role of 11β-HSD-1 in the pathogenesis ofthe metabolic syndrome is extensive (Masuzaki, et al. Science. 294:2166-2170, 2001; Paterson, J. M., et al.; Proc Natl. Acad. Sci. USA.101: 7088-93, 2004; Montague and O'Rahilly. Diabetes. 49: 883-888,2000). Therefore, administration of a therapeutically effective amountof an 11β-HSD-1 inhibitor may treat, control, ameliorate, delay, orprevent the onset of obesity. Long-term treatment with an 11β-HSD-1inhibitor may also be useful in delaying the onset of obesity, orperhaps preventing it entirely if the patients use an 11β-HSD-1inhibitor in combination with controlled diet, exercise, or incombination or sequence with other pharmacological approaches.

By reducing insulin resistance and/or maintaining serum glucose atnormal concentrations and/or reducing obesity compounds of the presentinvention also have utility in the treatment and prevention ofconditions that accompany Type 2 diabetes and insulin resistance,including the metabolic syndrome or syndrome X, obesity, reactivehypoglycemia, and diabetic dyslipidemia.

11β-HSD-1 is present in multiple tissues, including vascular smoothmuscle, where local glucocorticoid levels that are thought to increaseinsulin resistance, leading to reductions in nitric oxide production,and potentiation of the vasoconstrictive effects of both catecholaminesand angiotensin II (M. Pirpiris et al., Hypertension, 19:567-574, 1992,C. Kornel et al., Steroids, 58: 580-587, 1993, B. R. Walker and B. C.Williams, Clin. Sci. 82:597-605, 1992; Hodge, G. et al Exp. Physiol 87:1-8, 2002). High levels of cortisol in tissues where themineralocorticoid receptor is present may lead to hypertension, asobserved in Cushing's patients (See, D. N. Orth, N. Engl. J. Med.332:791-803, 1995, M. Boscaro, et al., Lancet, 357: 783-791, 2001, X.Bertagna, et al, Cushing's Disease. In: Melmed S., Ed. The Pituitary.2^(nd) ed. Malden, Mass.: Blackwell; 592-612, 2002). Transgenic miceoverexpressing 11β-HSD-1 in liver and fat are also hypertensive, aphenotype believed to result from glucocorticoid activation of the reninangiotensin system (Paterson, J. M. et al, PNAS. 101: 7088-93, 2004;Masuzaki, H. et al, J. Clin. Invest. 112: 83-90, 2003). Therefore,administration of a therapeutically effective dose of an 11β-HSD-1inhibitor may treat, control, ameliorate, delay, or prevent the onset ofhypertension.

Cushing's syndrome is a life-threatening metabolic disordercharacterized by sustained and elevated glucocorticoid levels caused bythe endogenous and excessive production of cortisol from the adrenalglands. Typical Cushingoid characteristics include central obesity,diabetes and/or insulin resistance, moon face, buffalo hump, skinthinning, dyslipidemia, osteoporosis, reduced cognitive capacity,dementia, hypertension, sleep deprivation, and atherosclerosis amongothers (Principles and Practice of Endocrinology and Metabolism. Editedby Kenneth Becker, Lippincott Williams and Wilkins Publishers,Philadelphia, 2001; pg 723-8). The same characteristics can also arisefrom the exogenous administration of high doses of exogenousglucocorticoids, such as prednisone or dexamethasone, as part of ananti-inflammatory treatment regimen. Endogenous Cushings typicallyevolves from pituitary hyperplasia, some other ectopic source of ACTH,or from an adrenal carcinoma or nodular hyperplasia. Administration of atherapeutically effective dose of an 11β-HSD-1 inhibitor may reducelocal glucocorticoid concentrations and therefore treat, control,ameliorate, delay, or prevent the onset of Cushing's disease and/orsimilar symptoms arising from glucocorticoid treatment.

11β-HSD-1 is expressed in mammalian brain, and published data indicatesthat glucocorticoids may cause neuronal degeneration and dysfunction,particularly in the aged (de Quervain et al.; Hum Mol. Genet. 13: 47-52,2004; Belanoffet al. J. Psychiatr Res. 35: 127-35, 2001). Evidence inrodents and humans suggests that prolonged elevation of plasmaglucocorticoid levels impairs cognitive function that becomes moreprofound with aging. (Issa, A. M. et al. J. Neurosci. 10: 3247-54, 1990;Lupien, S. J et al. Nat. Neurosci. 1: 69-73, 1998; Yau, J. L. W. et al.,Proc Natl Acad Sci USA. 98: 4716-4712, 2001). Thekkapat et al hasrecently shown that 11β-HSD-1 mRNA is expressed in human hippocampus,frontal cortex and cerebellum, and that treatment of elderly diabeticindividuals with the non-selective HSD1/2 inhibitor carbenoxoloneimproved verbal fluency and memory (Proc Natl Acad Sci USA. 101: 6743-9,2004). Additional CNS effects of glucocorticoids includeglucocorticoid-induced acute psychosis which is of major concern tophysicians when treating patients with these steroidal agents (Wolkowitzet al.; Ann NY Acad. Sci. 1032: 191-4, 2004). Conditional mutagenesisstudies of the glucocorticoid receptor in mice have also providedgenetic evidence that reduced glucocorticoid signaling in the brainresults in decreased anxiety (Tronche, F. et al. (1999) Nature Genetics23: 99-103). Therefore, it is expected that potent, selective 11β-HSD-1inhibitors would treat, control, ameliorate, delay, or prevent the onsetof cognitive decline, dementia, steroid-induced acute psychosis,depression, and/or anxiety.

In Cushing's patients, excess cortisol levels contributes to thedevelopment of hypertension, dyslipidemia, insulin resistance, andobesity, conditions characteristic of metabolic syndrome (Orth, D. N. etal N. Engl. J. Med. 332:791-803, 1995; Boscaro, M. et al., Lancet, 357:783-791, 2001, Bertagna, X. et al, Cushing's Disease. In: Melmed S., Ed.The Pituitary. 2^(nd) ed. Malden, Mass.: Blackwell; 592-612, 2002).Hypertension and dyslipidemia are also associated with development ofatherosclerosis. 11β-HSD-1 knockout mice are resistant to thedyslipidemic effects of a high fat diet and have an improved lipidprofile vs wild type controls (Morton N. M. et al, JBC, 276:41293-41300, 2001), and mice which overexpress 11β-HSD-1 in fat exhibitthe dyslipidemic phenotype characteristic of metabolic syndrome,including elevated circulating free fatty acids, and triclylgerides(Masuzaki, H., et al Science. 294: 2166-2170, 2001). Administration of aselective 1 (3-HSD-1 inhibitor has also been shown to reduce elevatedplasma triglycerides and free fatty acids in mice on a high fat diet,and significantly reduce aortic content of cholesterol esters, andreduce progression of atherosclerotic plaques in mice(Hermanowski-Vosatka, A. et al. J. Exp. Med. 202: 517-27, 2005). Theadministration of a therapeutically effective amount of an 11β-HSD-1inhibitor would therefore be expected to treat, control, ameliorate,delay, or prevent the onset of dyslipidemia and/or atherosclerosis.

Glucocorticoids are known to cause a variety of skin related sideeffects including skin thinning, and impairment of wound healing(Anstead, G. Adv Wound Care. 11: 277-85, 1998; Beer, et al.; Vitam Horm.59: 217-39, 2000). 11β-HSD-1 is expressed in human skin fibroblasts, andit has been shown that the topical treatment with the non-selectiveHSD1/2 inhibitor glycerrhetinic acid increases the potency of topicallyapplied hydrocortisone in a skin vasoconstrictor assay (Hammami, M M,and Siiteri, P K. J. Clin. Endocrinol. Metab. 73: 326-34, 1991).Advantageous effects of selective 11β-HSD-1 inhibitors such as BVT.2733on wound healing have also been reported (WO 2004/11310). High levels ofglucocorticoids inhibit blood flow and formation of new blood vessels tohealing tissues. In vitro and in vivo models of angiogenesis have shownthat systemic antagonism with the glucocorticoid receptor RU-486enhances angiogenesis in subcutaneous sponges as well as in mousemyocardium following coronary artery ligation (Walker, et al, PNAS, 102:12165-70, 2005). 11β-HSD-1 knockout mice also showed enhancedangiogenesis in vitro and in vivo within sponges, wounds, and infarctedmyocardium. It is therefore expected that potent, selective 11β-HSD-1inhibitors would treat, control, ameliorate, delay, or prevent the onsetof skin thinning and/or promote wound healing and/or angiogenesis.

Although cortisol is an important and well-recognized anti-inflammatoryagent (J. Baxer, Pharmac. Ther., 2:605-659, 1976), if present in largeamount it also has detrimental effects. In certain disease states, suchas tuberculosis, psoriasis and stress in general, high glucocorticoidactivity shifts the immune response to a humoral response, when in facta cell based response may be more beneficial to patients. Inhibition of11β-HSD-1 activity may reduce glucocorticoid levels, thereby shiftingthe immuno response to a cell based response. (D. Mason, ImmunologyToday, 12: 57-60, 1991, G. A. W. Rook, Baillier's Clin. Endocrinol.Metab. 13: 576-581, 1999). Therefore, administration of 11β-HSD-1specific inhibitors could treat, control, ameliorate, delay, or preventthe onset of tuberculosis, psoriasis, stress, and diseases or conditionswhere high glucocorticoid activity shifts the immune response to ahumoral response.

One of the more significant side effects associated with topical andsystemic glucocorticoid therapy is glaucoma, resulting in seriousincreases in intraocular pressure, with the potential to result inblindness (Armaly et al.; Arch Ophthalmol. 78: 193-7, 1967; Stokes etal.; Invest Ophthalmol Vis Sci. 44: 5163-7, 2003;). The cells thatproduce the majority of aqueous humor in the eye are the nonpigmentedepithelial cells (NPE). These cells have been demonstrated to express11-HSD-1, and consistent with the expression of 11β-HSD-1, is thefinding of elevated ratios of cortisol:cortisone in the aqueous humor(Rauz et al. Invest Ophthalmol Vis Sci. 42: 2037-2042, 2001).Furthermore, it has been shown that patients who have glaucoma, but whoare not taking exogenous steroids, have elevated levels of cortisol vs.cortisone in their aqueous humor (Rauz et al. QJM. 96: 481-490, 2003.)Treatment of patients with the nonselective HSD1/2 inhibitorcarbenoxolone for 4 or 7 days significantly lowered intraocular pressureand local cortisol generation within the eye (Rauz et al.; QJM. 96:481-490, 2003.). It is therefore expected that potent, selective11β-HSD-1 inhibitors would treat, control, ameliorate, delay, or preventthe onset of glaucoma.

Glucocorticoids (GCs) are known to increase bone resorption and reducebone formation in mammals (Turner et al. Calcif Tissue Int. 54: 311-5,1995; Lane, N E et al. Med Pediatr Oncol. 41: 212-6, 2003). 11β-HSD-1mRNA expression and reductase activity have been demonstrated in primarycultures of human osteoblasts in homogenates of human bone (Bland etal.; J. Endocrinol. 161: 455-464, 1999; Cooper et al.; Bone, 23:119-125, 2000). In surgical explants obtained from orthopedicoperations, 11β-HSD-1 expression in primary cultures of osteoblasts wasfound to be increased approximately 3-fold between young and old donors(Cooper et al.; J. Bone Miner Res. 17: 979-986, 2002). Glucocorticoids,such as prednisone and dexamethasone, are also commonly used to treat avariety of inflammatory conditions including arthritis, inflammatorybowl disease, and asthma. These steroidal agents have been shown toincrease expression of 11β-HSD-1 mRNA and activity in human ostcoblasts(Cooper et al.; J. Bone Miner Res. 17: 979-986, 2002). These studiessuggest that 11β-HSD-1 plays a potentially important role in thedevelopment of bone-related adverse events as a result of excessiveglucocorticoid levels or activity. Bone samples taken from healthy humanvolunteers orally dosed with the non-selective HSD1/2 inhibitorcarbenoxolone showed a significant decrease in markers of boneresorption (Cooper et al.; Bone. 27: 375-81, 2000). It is thereforeexpected that potent, selective 11β-HSD-1 inhibitors would treat,control, ameliorate, delay, or prevent the onset of conditions ofglucocorticoid-induced or age-dependent osteoporosis

The following diseases, disorders and conditions can be treated,controlled, prevented or delayed, by treatment with the compounds ofthis invention: (1) hyperglycemia, (2) low glucose tolerance, (3)insulin resistance, (4) lipid disorders, (5) hyperlipidemia, (6)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12), atherosclerosis and its sequelae, (13)vascular restensosis, (14) pancreatitis, (15) abdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropather, (19),neuropathy, (20) hypertension and other disorders where insulinresistance is a component, and (21) other diseases, disorders, andconditions that can benefit from reduced local glucocorticoid levels.

Neuronal Effects of 11β-HSD Inhibitors

Studies have shown that in homogenates of hippocampus, bothdehydrogenation and reduction occur (V. Lakshmi, et al., Endocrinol.,128, 1741-1748, 1991) and that 11β-HSD-1 is expressed in mammalianbrain, and published data indicates that glucocorticoids may causeneuronal degeneration and dysfunction (de Quervain et al., Hum Mol.Genet. 13: 47-52, 2004; Belanoff et al., J. Psychiatr Res., 35: 127-35,2001). Several studies have demonstrated 11β-HSD activity,immunoreactivity and mRNA expression in hippocampal neurons (M-P Moisan,et al., Endocrinol 127, 1450-1455, 1990; V. Lakshmi, et al.,Endocrinol., 128, 1741-1748, 1991; R R Sakai, et al., JNeuroendocrinol., 4, 101-106, 1992). Administration of 11β-HSDinhibitors alters functional activity in the hippocampus in vivo (J RSeckl, et al., J Endocrinol 136, 471-477, 1993). Evidence in rodents andhumans suggests that prolonged elevation of plasma glucocorticoid levelsimpairs cognitive function that becomes more profound with aging (A. M.Issa et al., J. Neurosci., 10: 3247-3254, 1990, S. J. Lupien, et. al.,Nat. Neurosci., 1:69-73 1998, J. L. Yau et al., Neuroscience, 66:571-581, 1995). Chronic excessive cortisol levels in the brain mayresult in neuronal loss and neuronal dysfunction. (See, D. S. Kerr etal., Psychobiology 22: 123-133, 1994, C. Woolley, Brain Res. 531:225-231, 1990, P. W. Landfield, Science, 272: 1249-1251, 1996).Furthermore, glucocorticoid-induced acute psychosis exemplifies a morepharmacological induction of this response, and is of major concern tophysicians when treating patients with these steroidal agents (Wolkowitzet al., Ann NY Acad. Sci. 1032: 191-4, 2004). Thekkapat et al haverecently shown that 11β-HSD-1 mRNA is expressed in human hippocampus,frontal cortex and cerebellum, and that treatment of elderly diabeticindividuals with the non-selective 11β-HSD-1 and 11β-HSD-2 inhibitorcarbenoxolone improved verbal fluency and memory (Proc Natl Acad SciUSA. 101: 6743-9, 2004). In addition, Walker et al have examined 11β-HSDactivity and its function in primary cultures of fetal hippocampus cells(U.S. Pat. No. 7,122,531; U.S. Pat. No. 7,087,400; Rajan V, et al., JNeurosci., 16, 65-70 (1996)), the contents of which are incorporatedherein by reference.

Therefore, the CNS diseases, disorders and conditions can be treated,controlled, prevented or delayed, by treatment with the compounds ofthis invention. Administration of a therapeutic dose of an 11β-HSD-1inhibitor may reduce, ameliorate, control and/or prevent disorders suchas the cognitive impairment associated with aging, neuronal dysfunction,dementia, steroid-induced acute psychosis, decline in cognitive functionin Alzheimer's and associated dementias, cognitive deficits associatedwith aging and neurodegeneration, dementia, senile dementia, AIDSdementia, depression, major depressive disorder, psychotic depression,treatment resistant depression, anxiety, panic disorder, post traumaticstress disorder, depression in Cushing's syndrome, steroid-induced acutepsychosis, cognitive deficits associated with diabetes, attentiondeficit disorder in general, attention deficit hyperactivity disorder(ADHD), mild cognitive impairment, and schizophrenia.

HSD-1 related disorders include, but are not limited to, non-insulindependent type 2 diabetes, insulin resistance, obesity, lipid disorders,metabolic syndrome, hyperglycemia, low glucose tolerance,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, high LDL levels, atherosclerosis and its sequelae, vascularrestensosis, pancreatitis, abdominal obesity, retinopathy, nephropather,neuropathy, hypertension, other disorders where insulin resistance is acomponent, cognitive impairment associated with aging, neuronaldysfunction, dementia, steroid-induced acute psychosis, decline incognitive function in Alzheimer's disease and associated dementias,cognitive deficits associated with aging and neurodegeneration,dementia, senile dementia, AIDS dementia, anxiety, panic disorder, posttraumatic stress disorder, steroid-induced acute psychosis, cognitivedeficits associated with diabetes, attention deficit disorder ingeneral, attention deficit hyperactivity disorder (ADHD), mild cognitiveimpairment, schizophrenia, and depression including major depressivedisorder, psychotic depression, depression in Cushing's syndrome, andtreatment resistant depression.

Accordingly, an embodiment is a method of inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprisingadministering to a mammal, a therapeutically effective amount of acompound of formula (I). Another embodiment is treating orprophylactically treating the above disorders in a mammal. The disordersmay be mediated by excessive glucocorticoid action in a mammal.

Therapeutic Compositions-Administration-Dose Ranges

Therapeutic compositions of the present compounds comprise an effectiveamount of the same formulated with one or more therapeutically suitableexcipients. The term “therapeutically suitable excipient,” as usedherein, generally refers to pharmaceutically suitable, solid, semi-solidor liquid fillers, diluents, encapsulating material, formulationauxiliary and the like. Examples of therapeutically suitable excipientsinclude, but are not limited to, sugars, cellulose and derivativesthereof, oils, glycols, solutions, buffers, colorants, releasing agents,coating agents, sweetening agents, flavoring agents, perfuming agentsand the like. Such therapeutic compositions may be administeredparenterally, intracisternally, orally, rectally, intraperitoneally orby other dosage forms known in the art.

Liquid dosage forms for oral administration include, but are not limitedto, emulsions, microemulsions, solutions, suspensions, syrups andelixirs. Liquid dosage forms may also contain diluents, solubilizingagents, emulsifying agents, inert diluents, wetting agents, emulsifiers,sweeteners, flavorants, perfuming agents and the like.

Injectable preparations include, but are not limited to, sterile,injectable, aqueous, oleaginous solutions, suspensions, emulsions andthe like. Such preparations may also be formulated to include, but arenot limited to, parenterally suitable diluents, dispersing agents,wetting agents, suspending agents and the like. Such injectablepreparations may be sterilized by filtration through abacterial-retaining filter. Such preparations may also be formulatedwith sterilizing agents that dissolve or disperse in the injectablemedia or other methods known in the art.

The absorption of the compounds of the present invention may be delayedusing a liquid suspension of crystalline or amorphous material havingpoor water solubility. The rate of absorption of the compounds generallydepends upon the rate of dissolution and crystallinity. Delayedabsorption of a parenterally administered compound may also beaccomplished by dissolving or suspending the compound in oil. Injectabledepot dosage forms may also be prepared by microencapsulating the samein biodegradable polymers. The rate of drug release may also becontrolled by adjusting the ratio of compound to polymer and the natureof the polymer employed. Depot injectable formulations may also preparedby encapsulating the compounds in liposomes or microemulsions compatiblewith body tissues.

Solid dosage forms for oral administration include, but are not limitedto, capsules, tablets, gels, pills, powders, granules and the like. Thedrug compound is generally combined with at least one therapeuticallysuitable excipient, such as carriers, fillers, extenders, disintegratingagents, solution retarding agents, wetting agents, absorbents,lubricants and the like. Capsules, tablets and pills may also containbuffering agents. Suppositories for rectal administration may beprepared by mixing the compounds with a suitable non-irritatingexcipient that is solid at ordinary temperature but fluid in the rectum.

The present drug compounds may also be microencapsulated with one ormore excipients. Tablets, dragees, capsules, pills and granules may alsobe prepared using coatings and shells, such as enteric and release orrate controlling polymeric and nonpolymeric materials. For example, thecompounds may be mixed with one or more inert diluents. Tableting mayfurther include lubricants and other processing aids. Similarly,capsules may contain opacifying agents that delay release of thecompounds in the intestinal tract.

Transdermal patches have the added advantage of providing controlleddelivery of the present compounds to the body. Such dosage forms areprepared by dissolving or dispensing the compounds in suitable medium.Absorption enhancers may also be used to increase the flux of thecompounds across the skin. The rate of absorption may be controlled byemploying a rate controlling membrane. The compounds may also beincorporated into a polymer matrix or gel.

For a given dosage form, disorders of the present invention may betreated, prophylatically treated, or have their onset delayed in apatient by administering to the patient a therapeutically effectiveamount of compound of the present invention in accordance with asuitable dosing regimen. In other words, a therapeutically effectiveamount of any one of compounds of formulas I thru IX is administered toa patient to treat and/or prophylatically treat disorders modulated bythe 11-beta-hydroxysteroid dehydrogenase type 1 enzyme. The specifictherapeutically effective dose level for a given patient population maydepend upon a variety of factors including, but not limited to, thespecific disorder being treated, the severity of the disorder; theactivity of the compound, the specific composition or dosage form, age,body weight, general health, sex, diet of the patient, the time ofadministration, route of administration, rate of excretion, duration ofthe treatment, drugs used in combination, coincidental therapy and otherfactors known in the art.

The present invention also includes therapeutically suitable metabolitesformed by in vivo biotransformation of any of the compounds of formula Ithru IX. The term “therapeutically suitable metabolite”, as used herein,generally refers to a pharmaceutically active compound formed by the invivo biotransformation of compounds of formula I thru IX. For example,pharmaceutically active metabolites include, but are not limited to,compounds made by adamantane hydroxylation or polyhydroxylation of anyof the compounds of formulas I thru IX. A discussion ofbiotransformation is found in Goodman and Gilman's, The PharmacologicalBasis of Therapeutics, seventh edition, MacMillan Publishing Company,New York, N.Y., (1985).

The total daily dose (single or multiple) of the drug compounds of thepresent invention necessary to effectively inhibit the action of11-beta-hydroxysteroid dehydrogenase type 1 enzyme may range from about0.01 mg/kg/day to about 50 mg/kg/day of body weight and more preferablyabout 0.1 mg/kg/day to about 25 mg/kg/day of body weight. Treatmentregimens generally include administering from about 10 mg to about 1000mg of the compounds per day in single or multiple doses.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed aspects will be apparent to those skilledin the art. Such changes and modifications, including without limitationthose relating to the chemical structures, substituents, derivatives,intermediates, syntheses, formulations and/or methods of use of theinvention, may be made without departing from the spirit and scopethereof.

What is claimed is:
 1. A method for treating a patient suffering from aglucocorticoid-related central nervous system disorder, comprisingadministering to the patient an effective amount of a selectiveinhibitor of 11-beta-hydroxysteroid dehydrogenase Type 1 enzymeactivity, wherein the inhibitor is a compound according to formula (I),or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof,

wherein A¹, A², A³ and A⁴ are each individually selected from the groupconsisting of hydrogen, alkenyl, alkyl, alkyl-NH-alkyl, alkylcarbonyl,alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cyano, cycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxyalkyl,arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocycleoxyalkyl, heterocyclesulfonyl, halogen, haloalkyl,—NR⁵—[C(R⁶R⁷)]_(n)—C(O)—R⁸, —O—[C(R⁹R¹⁰)]_(p)—C(O)—R¹¹, —OR¹², —S-alkyl,—S(O)-alkyl, —N(R¹³R¹⁴), —CO₂R¹⁵, —C(O)—N(R¹⁶R¹⁷), —C(R¹⁸R¹⁹)—OR²⁰,—C(R²¹R²²)—N(R²³R²⁴), —C(═NOH)—N(H)₂, —C(R^(18a)R^(19a))—C(O)N(R²³R²⁴),—S(O)₂—N(R²⁵R²⁶), and —C(R^(18a)R^(19a))—S(O)₂—N(R²⁵R²⁶); R^(18a) andR^(19a) are each independently selected from the group consisting ofhydrogen and alkyl; n is 0 or 1; p is 0 or 1; D is a member selectedfrom the group consisting of a —O—, —S—, —S(O)— and —S(O)₂—; E is amember selected from the group consisting of alkyl, alkoxyalkyl,carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle,heterocyclealkyl, or R⁴ and E taken together with the atoms to whichthey are attached form a heterocycle; R¹ is a member selected from thegroup consisting of hydrogen and alkyl; R² is a member selected from thegroup consisting of hydrogen, alkyl and cycloalkyl; R³ and R⁴ are eachindependently selected from the group consisting of hydrogen, alkyl,carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R¹ andR⁴ taken together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle; R⁵ isa member selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl; R⁶ and R⁷ are each independently selected from thegroup consisting of hydrogen and alkyl, or R⁶ and R⁷ taken together withthe atom to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle; R⁸ is selected from the groupconsisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl,carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy,alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy,heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy,heterocycleoxyalkyl and —N(R²⁷R²⁸); R⁹ and R¹⁰ are each independentlyselected from the group consisting of hydrogen and alkyl, or R⁹ and R¹⁰taken together with the atom to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle; R¹¹ isselected from the group consisting of hydroxy and —N(R²⁹R³⁰); R¹² isselected from the group consisting of hydrogen, alkyl, carboxyalkyl,cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,heterocyclealkyl and heterocycleoxyalkyl; R¹³ and R¹⁴ are eachindependently selected from the group consisting of hydrogen, alkyl,alkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylsulfonyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, cycloalkylsulfonyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl,heterocycle, heterocyclealkyl, heterocycleoxyalkyl andheterocyclesulfonyl; R¹⁵ is selected from the group consisting ofhydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl; R¹⁶ and R¹⁷ are each independently selected fromthe group consisting of hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl,arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl,carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy,heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl,heterocycleoxy, heterocyclesulfonyl, hydroxy, and-alkyl-C(O)N(R²⁰¹R²⁰²), or, R¹⁶ and R¹⁷ taken together with the atom towhich they are attached form a heterocycle; R²⁰¹ and R²⁰² areindependently selected from the group consisting of hydrogen and alkyl;R¹⁸, R¹⁹ and R²⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl,carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heterocycle and heterocyclealkyl; R²¹ and R²² are each independentlyselected from the group consisting of hydrogen, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, cycloalkyl,carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl,heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle,heterocyclecarbonyl and heterocyclesulfonyl; R²³ and R²⁴ are eachindependently selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, alkoxy, alkylsulfonyl, aryl, arylcarbonyl, aryloxy,arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl,cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl,heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle,heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy,or, R²³ and R²⁴ taken together with the atom to which they are attachedform a ring selected from the group consisting of heteroaryl andheterocycle; R²⁵ and R²⁶ are each independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl,aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl,carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy,heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl,heterocycleoxy, heterocyclesulfonyl, and hydroxy, or, R²⁵ and R²⁶ takentogether with the atom to which they are attached form a heterocycle;R²⁷ and R²⁸ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl,cycloalkyloxy, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heteroarylsulfonyl,heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl,heterocyclesulfonyl and hydroxy, or, R²⁷ and R²⁸ taken together with theatom to which they are attached form a heterocycle; and R²⁹ and R³⁰ areeach independently selected from the group consisting of hydrogen,alkyl, alkoxy, alkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl,arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy,carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl,heterocyclesulfonyl, and hydroxy, or, R²⁹ and R³⁰ taken together withthe atom to which they are attached form a heterocycle; provided that,if R¹ is hydrogen; then at least one of A¹, A², A³ and A⁴ is nothydrogen.
 2. The method according to claim 2, wherein the inhibitor is atherapeutically suitable metabolite of a compound of formula (I).
 3. Themethod according to claim 1, wherein the inhibitor is a compoundselected from the group consisting ofE-4-[(2-methyl-2-phenoxypropanoyl)amino]adamantane-1-carboxamide;E-4-[(2-methyl-2-{[4-(trifluoromethyl)benzyl]oxy}propanoyl)amino]adamantane-1-carboxamide;E-4-({2-methyl-2-[(2-methylcyclohexyl)oxy]propanoyl}amino)adamantane-1-carboxylicacid;E-4-({(2-methyl-2-[(3-methylcyclohexyl)oxy]propanoyl}amino)adamantane-1-carboxylicacid;E-4-{[2-(cycloheptyloxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(cyclohexylmethoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-({2-methyl-2-[(4-methylcyclohexyl)oxy]propanoyl}amino)adamantane-1-carboxamide;E-4-[(2-phenoxypropanoyl)amino]adamantane-1-carboxamide;E-4-{[2-methyl-2-(2-methylphenoxy)propanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-methyl-2-(4-methylphenoxy)propanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(2-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(2-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(4-methoxyphenoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxamide;E-4-({2-methyl-2-[3-(trifluoromethyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;E-4-{[2-(3-methoxyphenoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxamide;E-2-(4-chloro-phenoxy)-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide;E-{[2-methyl-2-(4-methylphenoxy)propanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(3-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-({2-methyl-2-[4-(trifluoromethoxy)phenoxy]propanoyl}amino)adamantane-1-carboxamide;E-4-{[2-(3-bromophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;4-({[((E)-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)carbonyl]amino}methyl)benzoic acid;E-4-{[2-(2,3-dimethylphenoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxylicacid; tert-butyl4-(2-{[(E)-5-(aminocarbonyl)-2-adamantyl]amino}-1,1-dimethyl-2-oxoethoxy)phenylcarbamate;E-N-[4-(aminocarbonyl)benzyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-N-[4-(aminocarbonyl)methyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;3-({[((E)-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)carbonyl]amino}methyl)benzoic acid;E-4-({2-[(5-bromopyridin-2-yl)oxy]-2-methylpropanoyl}amino)adamantane-1-carboxamide;E-4-{[2-(2-cyanophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(4-hydroxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;((E)-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)aceticacid;N-[(E)-5-(2-amino-2-oxoethyl)-2-adamantyl]-2-(4-chlorophenoxy)-2-methylpropanamide;2-(4-chlorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-ylmethyl)-2-adamantyl]propanamide;N-{(E)-5-[(aminosulfonyl)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide;N-{(E)-5-[(Z)-amino(hydroxyimino)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide;E-N-[4-(aminosulfonyl)benzyl]-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-N-(4-{[(methylsulfonyl)amino]carbonyl}benzyl)adamantane-1-carboxamide;E-4-({2-[(4-chlorophenyl)thio]-2-methylpropanoyl}amino)adamantane-1-carboxylicacid;E-4-({2-[(4-methoxyphenyl)thio]-2-methylpropanoyl}amino)adamantane-1-carboxamideamide;E-4-({2-[(4-methoxyphenyl)sulfinyl]-2-methylpropanoyl)}amino)adamantane-1-carboxamide;E-4-({2-[(4-methoxyphenyl)sulfonyl]-2-methylpropanoyl}amino)adamantane-1-carboxamide;E-4-({2-[4-chloro-2-(pyrrolidin-1-ylsulfonyl)phenoxy]-2-methylpropanoyl}amino)adamantane-1-carboxamide;E-4-({2-methyl-2-[4-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;E-4-({2-methyl-2-[2-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;E-4-[(2-{4-chloro-2-[(diethylamino)sulfonyl]phenoxy}-2-methylpropanoyl)amino]adamantane-1-carboxamide;E-4-({2-methyl-2-[4-(pyrrolidin-1-ylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;2-(2-chloro-4-fluorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamide;2-(2-chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2-adamantyl]propanamide;2-(2-chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylthio)-2-adamantyl]propanamide;2-(2-chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylsulfonyl)-2-adamantyl]propanamide;2-(2-chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylsulfinyl)-2-adamantyl]propanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-2-methylpropanamide;E-4-(([1-(4-chlorophenoxy)cyclobutyl]carbonyl)amino)adamantane-1-carboxamide;4-[({[((E)-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)methyl]sulfonyl}amino)methyl]benzoicacid;2-(4-chlorophenoxy)-N-[(E)-5-(1H-imidazol-2-yl)-2-adamantyl]-2-methylpropanamide;(2E)-3-((E)-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)acrylicacid;(E)-4-[(2-methyl-2-{[5-(1H-pyrazol-1-yl)pyridin-2-yl]oxy}propanoyl)amino]adamantane-1-carboxamide;2-(4-chlorophenoxy)-N-[(E)-5-isoxazol-5-yl-2-adamantyl]-2-methylpropanamide;2-(4-chlorophenoxy)-2-methyl-N-{(E)-5-[(2-morpholin-4-ylethoxy)methyl]-2-adamantyl}propanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(2-chlorophenoxy)-2-methylpropanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-methyl-2-(2-methylphenoxy)propanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-methyl-2-(4-methylphenoxy)propanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethyl)phenoxy]propanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-methyl-2-[2-(trifluoromethoxy)phenoxy]propanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(2-chloro-4-fluorophenoxy)-2-methylpropanamide;E-4-{[2-(2-chlorophenoxy)-2-methyl-3-phenylpropanoyl]amino}adamantane-1-carboxamide;2-(4-chlorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamide;E-4-({2-methyl-2-[(5-morpholin-4-ylpyridin-2-yl)oxy]propanoyl}amino)adamantane-1-carboxamide;E-4-{[2-methyl-2-(pyridin-2-yloxy)propanoyl]amino)}adamantane-1-carboxamide;2-(4-chlorophenoxy)-2-methyl-N-{E)-5-[(methylamino)sulfonyl]-2-adamantyl)}propanamide;3-((E)-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-1-adamantyl)propanoicacid;2-(4-chlorophenoxy)-N-{(E)-5-[(dimethylamino)sulfonyl]-2-adamantyl}-2-methylpropanamide;E-4-[(2-{[5-(1H-imidazol-1-yl)pyridin-2-yl]oxy}-2-methylpropanoyl)amino]adamantane-1-carboxamide;2-(4-chlorophenoxy)-2-methyl-N-[(E)-5-(1H-pyrazol-3-yl)-2-adamantyl]propanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(3-chlorophenoxy)-2-methylpropanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-methyl-2-(3-methylphenoxy)propanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(2-methoxyphenoxy)-2-methylpropanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(3-methoxyphenoxy)-2-methylpropanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-methoxyphenoxy)-2-methylpropanamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-cyanophenoxy)-2-methylpropanamide;E-4-{[2-methyl-2-(2-methylphenoxy)propanoyl]amino}adamantane-1-carboxamide;E-4-{[2-methyl-2-(3-methylphenoxy)propanoyl]amino}adamantane-1-carboxamide;E-4-[(2-methyl-2-{[(1S,2S)-2-methylcyclohexyl]oxy}propanoyl)amino]adamantane-1-carboxylicacid;E-4-({2-methyl-2-[(2-methylcyclohexyl)oxy]propanoyl)}amino)adamantane-1-carboxamideE-4-{[2-(cycloheptyloxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(cyclohexylmethoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxamide;E-4-({2-methyl-2-[(3-methylcyclohexyl)oxy]propanoyl}amino)adamantane-1-carboxamide;E-4-{[2-(2-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;4-{[({(E)-4-[(2-methyl-2-phenoxypropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoicacid;E-4-({2-[(4,4-dimethylcyclohexyl)oxy]-2-methylpropanoyl}amino)adamantane-1-carboxylicacid;E-4-{[2-methyl-2-(1,2,3,4-tetrahydronaphthalen-2-yloxy)propanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(4-bromophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-methyl-2-(1-naphthyloxy)propanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(2,3-dichlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(2,4-dichlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(2,5-dichlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(2,4-dimethylphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(2,5-dimethylphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-methyl-2-(2-naphthyloxy)propanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(4-bromo-2-fluorophenoxy)-2-methylpropanoyl]amino)}adamantane-1-carboxylicacid;E-4-({2-methyl-2-[(7-methyl-2,3-dihydro-1H-inden-4-yl)oxy]propanoyl)}amino)adamantane-1-carboxylicacid;E-4-{[2-(4-bromo-2-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(1,1′-biphenyl-3-yloxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-(2-bromophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;E-N-[4-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenoxypropanoyl)amino]adamantane-1-carboxamide;E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-N-(1,3-thiazol-5-ylmethyl)adamantane-1-carboxamide;E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-N-(pyridin-4-ylmethyl)adamantane-1-carboxamide;E-4-{[2-(4-aminophenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-({2-methyl-2-[2-(trifluoromethoxy)phenoxy]propanoyl}amino)adamantane-1-carboxamide;E-4-({2-methyl-2-[2-(trifluoromethyl)phenoxy]propanoyl)}amino)adamantane-1-carboxamide;E-4-({2-methyl-2-[4-(pyrrolidin-1-ylsulfonyl)phenoxy]propanoyl}amino)adamantane-1-carboxamide;2-(2-chloro-4-fluorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamide;2-(2-chloro-4-fluorophenoxy)-N-[(E)-5-cyano-2-adamantyl]-2-methylpropanamide;E-4-[(2-methyl-2-{4-[(trifluoroacetyl)amino]phenoxy}propanoyl)amino]adamantane-1-carboxamide;E-4-{[2-(3-bromo-4-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(2,5-dibromo-4-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(2-bromo-4-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(2-chloro-4-fluorophenoxy)-2-methylpropanoyl]amino}-N,N-dimethyladamantane-1-carboxamide;2-(4-chlorophenoxy)-N-((E)-5-{[(4-methoxy-6-methylpyrimidin-2-yl)amino]methyl}-2-adamantyl)-2-methylpropanamide;E-4-{[2-(4-{[(tert-butylamino)carbonyl]amino}phenoxy)-2-methylpropanoyl]amino}adamantane-1-carboxamide;ethyl4-(2-{[(E)-5-(aminocarbonyl)-2-adamantyl]amino}-1,1-dimethyl-2-oxoethoxy)phenylcarbamate;E-4-[(2-methyl-2-{4-[(propylsulfonyl)amino]phenoxy}propanoyl)amino]adamantane-1-carboxamide;E-4-[(2-{4-[(3,3-dimethylbutanoyl)amino]phenoxy})-2-methylpropanoyl)amino]adamantane-1-carboxamide;E-4-{[2-methyl-2-(phenylsulfinyl)propanoyl]amino}adamantane-1-carboxylicacid;E-4-{[2-methyl-2-(phenylsulfonyl)propanoyl]amino}adamantane-1-carboxylicacid;N-[(E)-5-cyano-2-adamantyl]-2-[(4-methoxyphenyl)sulfonyl]-2-methylpropanamide;2-[(4-methoxyphenyl)sulfonyl]-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2-adamantyl]propanamide;andE-4-({2-[4-(benzyloxy)phenoxy]-2-methylpropanoyl}amino)adamantane-1-carboxamide;or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof.
 4. The method of claim 1 for treating orprophylactically treating disorders in a mammal.
 5. The method of claim4, wherein the disorders are mediated by excessive glucocorticoid actionin a mammal.
 6. The method of claim 4 for treating a patient sufferingfrom a glucocorticoid-related central nervous system disorder.
 7. Themethod of claim 4, wherein the disorder is selected from the groupconsisting of decline in cognitive function in Cushing's syndrome, noninsulin dependent type 2 diabetes, insulin resistance, obesity, lipiddisorders, metabolic syndrome, hypertension, Alzheimer's and associateddementias, cognitive deficits associated with aging andneurodegeneration, dementia, senile dementia, AIDS dementia, majordepressive disorder, psychotic depression, treatment resistantdepression, anxiety, panic disorder, post traumatic stress disorder,depression in Cushing's syndrome, steroid-induced acute psychosis,cognitive deficits associated with diabetes, attention deficit disorderin general, attention deficit hyperactivity disorder (ADHD), mildcognitive impairment, neuronal dysfunction, and schizophrenia.
 8. Themethod of claim 4, wherein the disorder is selected from the groupconsisting of non insulin dependent type 2 diabetes, insulin resistance,obesity, lipid disorders, metabolic syndrome, and hypertension.
 9. Themethod of claim 4, wherein the disorder is selected from the groupconsisting of Cushing's syndrome, decline in cognitive function inCushing's syndrome, Alzheimer's disease and associated dementias,cognitive deficits associated with aging and neurodegeneration,dementia, senile dementia, AIDS dementia, major depressive disorder,psychotic depression, treatment resistant depression, anxiety, panicdisorder, post traumatic stress disorder, depression in Cushing'ssyndrome, steroid-induced acute psychosis, cognitive deficits associatedwith diabetes, attention deficit disorder in general, attention deficithyperactivity disorder (ADHD), mild cognitive impairment, neuronaldysfunction, and schizophrenia.
 10. The method of claim 4, wherein thedisorder is Alzheimer's disease.
 11. The method of claim 4, wherein thedisorder is decline in cognitive function in Alzheimer's and associateddementias.
 12. The method of claim 4, wherein the disorder is cognitivedeficits associated with aging or neurodegeneration.
 13. The method ofclaim 4, wherein the disorder is dementia, senile dementia or AIDSdementia.
 14. The method of claim 4, wherein the disorder is depression.15. The method of claim 14, wherein the depression is major depressivedisorder, psychotic depression, depression in Cushing's syndrome, ortreatment resistant depression.
 16. The method of claim 4, wherein thedisorder is anxiety, panic disorder, post traumatic stress disorder, orsteroid-induced acute psychosis.
 17. The method of claim 4, wherein thedisorder is cognitive deficits associated with diabetes, attentiondeficit disorder in general, attention deficit hyperactivity disorder(ADHD), or mild cognitive impairment.
 18. The method of claim 4, whereinthe disorder is schizophrenia.